WO2021130731A1 - Substituted tricyclic compounds - Google Patents

Substituted tricyclic compounds Download PDF

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Publication number
WO2021130731A1
WO2021130731A1 PCT/IB2020/062462 IB2020062462W WO2021130731A1 WO 2021130731 A1 WO2021130731 A1 WO 2021130731A1 IB 2020062462 W IB2020062462 W IB 2020062462W WO 2021130731 A1 WO2021130731 A1 WO 2021130731A1
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WIPO (PCT)
Prior art keywords
compound
ethyl
quinazolin
difluoro
amino
Prior art date
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PCT/IB2020/062462
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English (en)
French (fr)
Inventor
Sanjay Pralhad KURHADE
Prathap Sreedharan Nair
Sachin Sethi
Manojkumar Ramprasad SHUKLA
Milind Dattatraya Sindkhedkar
Venkata P. Palle
Rajender Kumar Kamboj
Samiron Phukan
Pradeep Rangrao PATIL
Sayyed MAJID
Ramesh PHADATARE
Navnath WALKE
Vipul PACHPUTE
Balasaheb GORE
Vikas TAMBE
Rohan LIMAYE
Avadhut BHOSALE
Sachin MAHANGARE
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Lupin Limited
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Publication date
Priority to CA3165864A priority Critical patent/CA3165864A1/en
Priority to JP2022539232A priority patent/JP2023514019A/ja
Priority to MX2022008066A priority patent/MX2022008066A/es
Priority to IL294198A priority patent/IL294198A/en
Application filed by Lupin Limited filed Critical Lupin Limited
Priority to CN202080097766.XA priority patent/CN115605476B/zh
Priority to EP20842043.0A priority patent/EP4081521A1/en
Priority to BR112022012641A priority patent/BR112022012641A2/pt
Priority to PE2022001331A priority patent/PE20221283A1/es
Priority to AU2020412429A priority patent/AU2020412429A1/en
Priority to CR20220363A priority patent/CR20220363A/es
Priority to KR1020227026096A priority patent/KR20220132543A/ko
Priority to US17/789,293 priority patent/US20230119316A1/en
Publication of WO2021130731A1 publication Critical patent/WO2021130731A1/en
Priority to ZA2022/07722A priority patent/ZA202207722B/en
Priority to CONC2022/0010460A priority patent/CO2022010460A2/es

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/20—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/20—Spiro-condensed systems

Definitions

  • the present invention is related to a compound of the general formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, its solvate, its combination with suitable medicament, its pharmaceutical composition, method of making of the compound, its use as SOS1 inhibitor, and its therapeutic utility in various pathological conditions.
  • RAS-family proteins (KRAS, HRAS and NRAs and their respective mutants) are small GTPases that exist in cells in either GTP-bound (inactive) or GDP-bound (active) states (Siqi Li et al, Nat. Rev. Cancer, 2018, 18(12):767-777).
  • the activity of RAS proteins is modulated by proteins known as GTPase Activating Proteins (GAPs) or Guanine Nucleotide
  • GEFs Exchange Factors
  • the GAP proteins belonging to the RAS family include members such as NF1, TSC2, IQGAP1, etc. which activate the GTPase function of the RAS proteins and thus terminate the signaling by catalyzing the hydrolysis of GTP to GDP.
  • the RAS family GEFs include proteins such as SOS1, SOS2, RASGRP, RASGRF2, etc. which activate the RAS proteins by exchanging GTP for GDP (Johannes L. Bos etal, Cell, 2007, 129(5):865-77).
  • Ras-GTP binds to effector proteins such as Raf and PI3K which in turn leads to activation of the RAF-MEK- ERK (MAPK) and PI3K-mTOR-AKT (PI3K) signaling pathways (Suzanne Schubbert et al., Nat. Rev. Cancer, 2007, 7(4):295-308). Triggering of one or more of these cellular signaling pathways leads to the initiation and maintenance of the oncogenic phenotype involving enhanced cell proliferation, increased cell survival, altered metabolism, angiogenesis, migratory potential and immune evasion eventually leading to establishment and metastasis of cancers (Yousef Ahmed Fouad et al., Am. J.
  • RAS proteins undergo point mutations at several amino acid residues - the key hot spots being positions G12, G13 and Q61. These mutations render the RAS proteins constitutively active since the proteins are predominantly in the active GTP -bound form (Ian A. Prior et al., Cancer Res.2012, 15; 72(10): 2457-2467; Adrienne D. Cox, et al., Nat. Rev. Drug. Discov., 2014, 13(11):828- 51).
  • SOS1 Son of Sevenless 1
  • DH Dbl homology domain
  • PH Pleckstrin homology domain
  • REM RAS exchanger motif
  • CDC25 homology domain
  • PxxP C-terminal proline rich domain
  • the catalytic site is preferentially bound by RAS-GDP whereas RAS-GTP binds with the allosteric site with better affinity than RAS-GDP (S. Mariana Margarit et al., Cell, 2003, 7;112(5):685-95; Hao-Hsuan Jeng et al., Nat. Commun., 2012; 3:1168). Furthermore, binding of oncogenic KRAS to SOS1 promotes the activation of wild type HRAS and NRAS (Hao-Hsuan Jeng etal., Nat. Commun., 2012;3:1168).
  • SOS1 The catalytic (guanine nucleotide exchange) function of SOS1 is critical for KRAS oncogenic activity in cancer cells (You X et al., Blood. 2018, 13;132(24):2575-2579; Erin Sheffels et al., Sci Signal. 2018, 4;11(546). pii: eaar8371). SOS1 plays a key role in signal transmission following cellular activation by Receptor Tyrosine Kinases (RTKs) (Frank McCormick et al., Nature, 1993, 6;363(6424):45-51; Stephane Pierre et al., Biochem Pharmacol. 2011, 1;82(9): 1049-56).
  • RTKs Receptor Tyrosine Kinases
  • SOS1 in the RAS-mediated signaling pathways make it an attractive target for cancer therapy.
  • Pharmacological intervention with SOS1 inhibitors has been shown to attenuate or eliminate the downstream effector events of the RAS-mediated pathways (Roman C. Hillig et al., Proc. Natl. Acad. Sci. U S A. 2019, 12;116(7):2551-2560; Chris R. Evelyn et al., J Biol Chem., 2015, 15; 290(20): 12879-98).
  • hereditary SOS1 mutations are implicated in the pathogenesis of RASopathies like e.g.
  • Noonan syndrome NS
  • cardio-facio-cutaneous syndrome CFC
  • hereditary gingival fibromatosis type 1 NS
  • hSOSl expression is significantly upregulated in whole blood cell extracts of pediatric patients with acute community -acquired Staphylococcus aureus infection and in patients with Acute Respiratory Distress Syndrome (ARDS)/Acute Lung Injury (ALI) and Sepsis (F.C. Baltanas, et al. BBA - Reviews on Cancer 1874 (2020) 188445).
  • the present invention provides compound of the general formula (I), its pharmaceutically acceptable salts, its tautomeric forms, its stereoisomers, its polymorphs, its solvates, its combinations with suitable other medicament or medicaments, its pharmaceutical compositions thereof, and its use thereof in treating various diseases or disorders including cancers, wherein, ring A, ring B, R 1 to R 4 , and n are as described hereinbelow.
  • the compounds of the present invention are potent inhibitors of SOS1.
  • a compound represented by the general formula (I) its tautomeric form, its stereoisomer, its polymorph, its solvate, its pharmaceutically acceptable salt, its combinations with suitable medicament and its pharmaceutical compositions.
  • the present invention provides a pharmaceutical composition, containing the compound of the general formula (I) as defined herein, its tautomeric form, and its stereoisomer, its polymorph, its solvate, or its pharmaceutically acceptable salt in combination with the usual pharmaceutically employed carriers, diluents, and the like are useful for the treatment of a disease or disorder mediated through SOS1.
  • the present invention provides a pharmaceutical composition, containing the compound of the general formula (I) as defined herein, its tautomeric form, its stereoisomer, its polymorph, its solvate, or its pharmaceutically acceptable salt in combination with the usual pharmaceutically employed carriers, diluents, and the like are useful for the treatment of a disease or disorder such as cancer, infectious disease or disorder, or RASopathy disease or disorder.
  • a disease or disorder such as cancer, infectious disease or disorder, or RASopathy disease or disorder.
  • the present invention provides the compound of formula I, its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, its solvate, its combination with suitable medicament, or its pharmaceutical composition for treating disease characterized by excessive or abnormal cell proliferation such as cancer.
  • the present invention provides the compound of formula I, its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, its solvate, its combination with suitable medicament, or its pharmaceutical composition for treating diseases like pancreatic cancer, lung cancer, colorectal cancer, class 3 BRAF-mutant cancers, hematological cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukaemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B cell lymphoma, esophageal cancer, chronic lymphocytic leukaemia, hepatocellular cancer, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer, Pure mucosal neuroma syndrome, Fibrous Epulis, and sarcomas.
  • diseases like pancreatic cancer, lung cancer, colorectal
  • the present invention provides the compound of formula I, its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, its solvate, its combination with suitable medicament, or its pharmaceutical composition for treating diseases such as Neurofibromatosis type 1 (NF1), Noonan Syndrome with Multiple Lentigines (NSML), Noonan-like/multiple giant cell lesion syndrome, Hereditary Gingival Fibromatosis (HGF), Capillary Malformation-Arteriovenous Malformation Syndrome (CM-AVM), Legius Syndrome, Acute Staphylococcus aureus infection (Pediatric Patients), Pure mucosal neuroma syndrome, Fibrous Epulis, Acute Respiratory Distress syndrome/Acute Lung injury and Sepsis, Costello Syndrome (CS), and Cardio-Facio-cutaneous Syndrome (CFC Syndrome).
  • diseases such as Neurofibromatosis type 1 (NF1), Noonan Syndrome with Multiple Lentigines (NSML), Noonan-like/multiple giant cell lesion syndrome, Her
  • the present invention provides the compound of formula I, its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, its solvate, its combination with suitable medicament, or its pharmaceutical composition for use in therapeutic regimens in the context of first line, second line, or any further line of treatments.
  • the present invention provides the compound of formula I, its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, its solvate, its combination with suitable medicament, or its pharmaceutical composition for use in the prevention, short-term or long term treatment of the above-mentioned diseases optionally in combination with radiotherapy and/or surgery.
  • the present invention provides the compound of formula I, its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, its solvate, its combination with suitable medicament, or its pharmaceutical composition for treating various cancers mentioned above which harbor hyperactive or aberrantly activated signaling pathways involving RAS and or SOS1 proteins.
  • the present invention provides use of the compound of formula I, its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, or its solvate in combination with other agents such as radiation, chemotherapeutic agents and/or targeted agents in multiple cancers and their subtypes as mentioned above.
  • the agents that can be used for combination therapy include targeted agents such as inhibitors of RTKs, cyclin-dependent kinase (CDK) inhibitors, Ser-Thr kinase inhibitors, non-receptor tyrosine kinase inhibitors, inhibitors of epigenetic mechanism such as histone methyltransferases (HMTs), DNA methyltransferases (DNMTs), protein arginine methyltransferases (PRMTs), RAS inhibitors, KRAS inhibitors, MEK inhibitors, ERK1/2 inhibitors, Focal Adhesion Kinase (FAK) inhibitors, PI3K inhibitors, AKT inhibitors, and mTOR inhibitors.
  • HMTs histone methyltransferases
  • DNMTs DNA methyltransferases
  • PRMTs protein arginine methyltransferases
  • RAS inhibitors KRAS inhibitors
  • MEK inhibitors MEK inhibitors
  • ERK1/2 inhibitors Focal Adhesion Kinas
  • the present invention is related to a compound of the general formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, its solvate, its combination with suitable one or more other medicaments, its pharmaceutical composition, method of making of the compound, its use as SOS1 inhibitor, and its therapeutic utility in treating, or ameliorating various pathological conditions.
  • the compound of formula (I) is as shown below:
  • Ring A is selected from aryl, heteroaryl, and heterocyclyl
  • Ring B is selected from substituted or unsubstituted 5 or 6 membered carbocyclic ring and substituted or unsubstituted 5 or 6 membered heterocyclic ring containing 1 to 3 heteroatoms independently selected from S, O, and N; when ring B is carbocyclic ring, it is substituted with 1 to 8 substituents independently selected from R c and
  • R d when ring B is heterocyclic ring, it is substituted with 1 to 7 substituents; when it is substituted on a ring nitrogen atom, it is substituted with substituents selected from R a and R b ; and when it is substituted on a ring carbon atom, it is substituted with substituents selected from R c and R d ;
  • R 1 is selected from hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl
  • R 2 and R 3 are independently selected from hydrogen, halogen, cyano, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl;
  • R 8 is selected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl;
  • R h and R' are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocyclyl; optionally R h and R' groups together with the nitrogen atom to which they are attached forming a substituted or unsubstituted heterocycle;
  • R j is selected from hydrogen, substituted or unsubstituted alkyl, alkyl substituted with substituted or unsubstituted cycloalkyl, and substituted or unsubstituted cycloalkyl;
  • R 5 is selected from hydrogen, alkyl, perhaloalkyl, and cycloalkyl
  • R 6 and R 6 * are each independently selected from hydrogen, alkyl, and cycloalkyl; or R 6 and R 6 * together with nitrogen to which they are attached form a heterocyclyl ring; and
  • R 7 is selected from alkyl and cycloalkyl.
  • ring A is aryl and heteroaryl.
  • ring A is phenyl and In any of the above embodiments, ring B is selected from
  • ring B is selected from In any of the above embodiments, R 1 is selected from substituted or unsubstituted alkyl and substituted or unsubstituted cycloalkyl.
  • R 1 is selected from methyl, ethyl, isopropyl, and cyclopropyl.
  • R 2 and R 3 are independently selected from hydrogen, halogen, and substituted or unsubstituted alkyl.
  • R 2 and R 3 are independently selected from hydrogen, fluorine, and methyl.
  • R 4 is selected from halogen, -NR e R f , substituted or unsubstituted alkyl, cycloalkyl substituted with substituted or unsubstituted alkyl, and substituted or unsubstituted heterocyclyl.
  • R 4 is selected from fluorine, -NH2, -CH3, -CF3, -CHF2,
  • R 1 and R b are independently selected from hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl.
  • R 1 and R b are independently selected from hydrogen, methyl, ethyl, isopropyl,
  • R c and R d are independently selected from hydrogen, methyl, isopropyl, ethyl, -CH2F, -CH2OMe, -OMe, -OH, fluorine, -OCH 2 CH 3 , -CF 3 , and -CH2CH2OMe; optionally R c and R d groups together with the carbon atom which they are attached forming cycloproyl ring, cyclopentyl ring, tetrahydropyran ring, tetrahydrofuran ring and N-methyl oxazolidinone ring.
  • R e and R f are selected from hydrogen.
  • R j is selected from hydrogen and alkyl. In certain embodiments, R j is selected from hydrogen, methyl, and ethyl.
  • the invention provides the compound of the general formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, or solvate thereof, wherein ring A is selected from aryl and heteroaryl; ring B is selected from
  • R 1 is selected from substituted or unsubstituted alkyl and substituted or unsubstituted cycloalkyl
  • R 2 and R 3 are independently selected from hydrogen, halogen, and substituted or unsubstituted alkyl
  • R 4 is selected from halogen, -NR'R * substituted or unsubstituted alkyl, cycloalkyl substituted with substituted or unsubstituted alkyl, and substituted or unsubstituted heterocyclyl
  • R a and R b are independently selected from hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl
  • the invention provides the compound of the general formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, or solvate thereof, wherein ring A is selected
  • R 1 is selected from methyl, ethyl, isopropyl, and cyclopropyl;
  • R 2 and R 3 are independently selected from hydrogen, fluorine, and methyl;
  • R 4 is selected from fluorine, -NH2, -CH3, -CF3, -CHF2,
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the general formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, or solvate thereof, and a pharmaceutically acceptable carrier.
  • the invention provides a method for the treatment and/or prevention of a disease, disorder, and/or a condition by inhibiting SOS1 in a subject, comprising administering to the subject a therapeutically effective amount of a compound of the general formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, or solvate thereof.
  • the invention provides a method for the treatment and/or prevention of a disease, disorder, and/or a condition by inhibiting the interaction of SOS1 and RAS family protein in a subject, comprising administering to the subject a therapeutically effective amount of a compound of the general formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, or solvate thereof.
  • the invention provides a method for the treatment and/or prevention of a disease, disorder, and/or a condition, wherein the said disease, disorder, and/or condition is a cancer.
  • a method for the treatment and/or prevention of a disease, disorder, and/or a condition is a cancer, wherein the cancer is selected from the group consisting of pancreatic cancer, lung cancer, colorectal cancer, class 3 BRAF-mutant cancers, hematological cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukaemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B cell lymphoma, esophageal cancer, chronic lymphocytic leukaemia, hepatocellular cancer, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer, Pure mucosal neuroma syndrome, Fibrous Epulis, and sarcomas.
  • pancreatic cancer lung cancer, colorectal cancer, class 3 BRAF-mutant cancers
  • the invention provides a method for the treatment and/or prevention of a disease, disorder, and/or a condition, wherein the said disease is Acute Staphylococcus aureus infection (Pediatric Patients), Acute Respiratory Distress syndrome/ Acute Lung injury, and Sepsis.
  • the invention provides a method for the treatment and/or prevention of a disease, disorder, and/or a condition, wherein the said disease, disorder, and/or condition is a RASopathy.
  • a method for the treatment and/or prevention of a disease, disorder, and/or a condition is a RASopathy, wherein the RASopathy is selected from the group consisting of Neurofibromatosis type 1 (NF1), Noonan Syndrome (NS), Noonan Syndrome with Multiple Lentigines (NSML), Capillary Malformation-Arteriovenous Malformation Syndrome (CM-AVM), Costello Syndrome (CS), Cardio-Facio- Cutaneous Syndrome (CFC), Legius Syndrome, Noonan-like/multiple giant cell lesion syndrome and Hereditary Gingival Fibromatosis (HGF) ⁇
  • the invention provides the method, wherein the compound of the general formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, or solvate thereof, is administered before, after, or together with at least one or more pharmacologically active substance.
  • the invention provides use of a compound of the general formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, or solvate thereof, for the treatment and/or prevention of a disease, disorder, and/or a condition by inhibiting SOS1 in a subject, comprising administering to the subject a therapeutically effective amount of a said compound.
  • the invention provides use of a compound of the general formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, or solvate thereof, for the treatment and/or prevention of a disease, disorder, and/or condition by inhibiting the interaction of SOS 1 and RAS family protein in a subject, comprising administering to the subject a therapeutically effective amount of a said compound.
  • the invention provides the use of a compound for the treatment and/or prevention of a disease, disorder, and/or condition, wherein the said disease, disorder, and/or condition is cancer.
  • the use of a compound for the treatment and/or prevention of a disease, disorder, and/or condition is cancer, wherein the cancer is selected from the group consisting of pancreatic cancer, lung cancer, colorectal cancer, class 3 BRAF-mutant cancers, hematological cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukaemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B cell lymphoma, esophageal cancer, chronic lymphocytic leukaemia, hepatocellular cancer, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer, Pure mucosal neuroma syndrome, Fibrous Epulis, and sarcomas.
  • the cancer is selected from the group consisting of pancreatic cancer, lung cancer, colorectal cancer, class 3 B
  • the invention provides the use of a compound for the treatment and/or prevention of a disease, disorder, and/or condition, wherein the said disease is Acute Staphylococcus aureus infection (Pediatric Patients), Acute Respiratory Distress syndrome/ Acute Lung injury, and Sepsis.
  • a disease is Acute Staphylococcus aureus infection (Pediatric Patients), Acute Respiratory Distress syndrome/ Acute Lung injury, and Sepsis.
  • the invention provides the use of a compound for the treatment and/or prevention of a disease, disorder, and/or condition, wherein the said the disease is a RASopathy.
  • the use of a compound for the treatment and/or prevention of a disease, disorder, and/or condition is a RASopathy, wherein the RASopathy is selected from the group consisting of Neurofibromatosis type 1 (NF1), Noonan Syndrome (NS), Noonan Syndrome with Multiple Lentigines (NSML), Capillary Malformation-Arteriovenous Malformation Syndrome (CM-AVM), Costello Syndrome (CS), Cardio-Facio- Cutaneous Syndrome (CFC), Legius Syndrome, Noonan-like/multiple giant cell lesion syndrome and Hereditary gingival fibromatosis (HGF).
  • NF1 Neurofibromatosis type 1
  • NS Noonan Syndrome
  • NML Noonan Syndrome with Multiple Lentigines
  • CM-AVM Capillary Malformation-Arteriovenous Malformation Syndrome
  • CS Costello Syndrome
  • CFC Cardio-Facio- Cutaneous Syndrome
  • Legius Syndrome Noonan-like/multiple giant cell lesion syndrome and Hereditary gingival
  • the invention provides the compound of the general formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, or solvate thereof, for treatment and/or prevention of cancer, wherein said compound is administered in combination with at least one more pharmacologically active substance.
  • the invention provides the compound of the general formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, or solvate thereof, for treatment and/or prevention of cancer, wherein the compound is administered before, after, or together with at least one other pharmacologically active substance.
  • a range of the number of atoms in a structure is indicated (e.g., a Ci to C20 alkyl etc.), it is specifically contemplated that any sub-range or individual number of carbon atoms falling within the indicated range also can be used.
  • a range of 1-6 carbon atoms (e.g., Ci to Ce), 2-6 carbon atoms (e.g., C2 to Ce), 3-6 carbon atoms (e.g., C3 to Ce), as used with respect to any chemical group (e.g., alkyl etc.) referenced herein encompasses and specifically describes 1, 2, 3, 4, 5, and/or 6 carbon atoms, as appropriate, as well as any sub-range thereof (e.g., 1-2 carbon atoms, 1-3 carbon atoms, 1-4 carbon atoms, 1-5 carbon atoms, 1-6 carbon atoms, 2-3 carbon atoms, 2-4 carbon atoms, 2-5 carbon atoms, 2-6 carbon atoms, 3-4 carbon atoms, 3-5 carbon atoms, 3-6 carbon atoms, 4-5 carbon atoms, 4-6 carbon atoms, as appropriate).
  • any chemical group e.g., alkyl etc.
  • alkyl means a straight chain or branched hydrocarbon containing from 1 to 20 carbon atoms.
  • the alkyl chain may contain 1 to 10 carbon atoms. More preferably, alkyl chain may contain up to 6 carbon atoms.
  • Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tot-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl.
  • haloalkyl as used herein means an alkyl group as defined hereinabove wherein at least one of the hydrogen atoms of the said alkyl group is substituted with halogen.
  • the haloalkyl group is exemplified by chloromethyl, 1-chloroethyl, and the like.
  • perhaloalkyV means an alkyl group as defined hereinabove wherein all the hydrogen atoms of the said alkyl group are substituted with halogen.
  • the perhaloalkyl group is exemplified by trifluoromethyl, pentafluoroethyl, and the like.
  • carrier or ‘carbocyclic ring’ as used herein, means a monocyclic, bicyclic, or tricyclic saturated or unsaturated non-aromatic ring system containing from 3 to 14 carbon atoms, preferably monocyclic cycloalkyl ring containing 3 to 6 carbon atoms.
  • monocyclic ring systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Bicyclic ring systems include monocyclic ring system fused across a bond with another cyclic system which may be an alicyclic ring or an aromatic ring.
  • Bicyclic rings also include spirocyclic systems wherein the second ring gets annulated on a single carbon atom.
  • Bicyclic ring systems are also exemplified by a bridged monocyclic ring system in which two non-adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge.
  • bicyclic ring systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane, bicyclo[3.3.2]decane, bicyclo[3.1.0]hexane, bicyclo[4.1.0]heptane, bicyclo[3.2.0]heptanes, octahydro-1H-indene, spiro[2.5]octane, spiro[4.5]decane, spiro[bicyclo[4.1.0]heptane-2,l '-cyclopentane], hexahydro-2H-spiro [cyclopropane- 1,1'- pentalene].
  • Tricyclic ring systems are the systems wherein the bicyclic systems as described above are further annulated with third ring, which may be an alicyclic ring or aromatic ring. Tricyclic ring systems are also exemplified by a bicyclic ring system in which two non-adjacent carbon atoms of the bicyclic ring are linked by a bond or an alkylene bridge. Representative examples of tricyclic-ring systems include, but are not limited to, tricyclo[3.3.1.1 3.7 ]nonane, and tricyclo[3.3.1.1 3.7 ]decane (adamantane).
  • cycloalkyl as used herein, means a monovalent carbocyclic ring.
  • aryl refers to a monovalent monocyclic, bicyclic or tricyclic aromatic hydrocarbon ring system. Examples of aryl groups include phenyl, naphthyl, anthracenyl, fluorenyl, indenyl, azulenyl, and the like.
  • Aryl group also include partially saturated bicyclic and tricyclic hydrocarbon ring systems with at least one aromatic ring, e.g. tetrahydro-naphthalene.
  • Aryl group also include bicyclic systems like 2,3-dihydro- indene-5-yl, and 2,3-dihydro-1-indenone-5-yl.
  • heteroaryl refers to a 5-14 membered monocyclic, bicyclic, or tricyclic ring system having 1-4 ring heteroatoms selected from O, N, or S, and the remainder ring atoms being carbon (with appropriate hydrogen atoms unless otherwise indicated), wherein at least one ring in the ring system is aromatic.
  • heteroaryl as used herein, also include partially saturated bicyclic and tricyclic aromatic ring system, e.g.
  • Heteroaryl groups may be optionally substituted with one or more substituents. In one embodiment, 0, 1, 2, 3, or 4 atoms of each ring of a heteroaryl group may be substituted by a substituent.
  • heteroaryl groups include, but not limited to, IH- 1 ,2,3-triazolyl, 2H- 1,2,3 -triazolyl, pyridyl, 1-oxo-pyridyl, furanyl, thienyl, pyrrolyl, oxazolyl, oxadiazolyl, imidazolyl, thiazolyl, isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, triazolyl, thiadiazolyl, isoquinolinyl, benzoxazolyl, benzofuranyl, indolizinyl, imidazopyridyl, imidazolyl, tetrazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl, indolyl,
  • heterocycle or ‘heterocyclic ring’ or ‘heterocyclyl’ as used herein, means a ‘carbocycle’ or ‘carbocyclic ring’ or ‘cycloalkyl’ group wherein one or more of the carbon atoms are replaced by heteroatoms/groups selected from N, S, SO2, and O.
  • the heterocycle may be connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the heterocycle.
  • Representative examples of monocyclic heterocycle include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl,
  • bicyclic heterocycle include, but are not limited to, 1,2,3,4-tetrahydroisoquinolin- 2-yl, 1,2,3,4-tetrahydroquinolm-1-yl, 1,3-benzodioxolyl, 1 ,3-benzodithiolyl, 2,3-dihydro-l,4-benzodioxinyl,
  • heterocycle also includes bridged and spiro heterocyclic systems such as azabicyclo[3.2.1]octane, azabicyclo[3.3.1]nonane, 8-oxa-3-azabicyclo[3.2.1]octan-3-yl, 3-oxa-8- azabicyclo[3.2.1]octan-8-yl, 6-oxa-3-azabicyclo[3.1.
  • halogen means fluorine, chlorine, bromine, or iodine.
  • oxo attached to carbon forms a carbonyl
  • oxo substituted on cyclohexane forms a cyclohexanone, and the like.
  • annulated means the ring system under consideration is either simulated with another ring at a carbon atom of the cyclic system or across a bond of the cyclic system as in the case of fused or spiro ring systems.
  • bridged means the ring system under consideration contain an alkylene bridge having 1 to 4 methylene units joining two non-adjacent ring atoms.
  • the compound of formula (Al) undergoes a metal catalyzed cross coupling with alkoxy vinyl stannane, e.g. tributyl(l-ethoxyvinyl)tin in presence of palladium catalysts such as Pd(PhgP)2Cl2, Pd2(dba)a and like; optionally using bases such as triethylamine, ⁇ , ⁇ -Diisopropylethylamine and like, in hydrocarbon solvents like toluene or ether solvents like 1,4-dioxane to furnish the alkoxy vinyl intermediate which in turn provide compound of formula (A2) in acidic condition by employing aqueous mineral acids such as hydrochloric acid in ether solvent such as THF, 1,4-dioxane and like.
  • aqueous mineral acids such as hydrochloric acid in ether solvent such as THF, 1,4-dioxane and like.
  • the similar transformation can be carried out by reaction of compound of formula (Al) with n-alkylvinyl ether using catalysts such as palladium ( ⁇ ) acetate and like, ligands such as 1 ,3-Bis(diphenylphosphino)propane and like, in presence of organic bases such as DIPEA, TEA and like in alcoholic solvents such as ethylene glycol and at elevated temperatures ,in solvents such as 1,4- dioxane, THF and mixtures thereof to give alkoxy vinyl intermediate which in turn provide compound of formula (A2) in acidic condition by employing aqueous mineral acids such as hydrochloric acid in ether solvent such as THF, 1,4-dioxane and like
  • the compound of formula (A2) was then reacted with corresponding chirally pure t-butanesulfmamide in presence of Lewis acid such as Titanium alkoxides e.g. titanium tetraethoxide, titanium isopropoxide and the like, in ether solvents such as 1,4-dioxane, THF and like, to obtain the compound of formula (A3).
  • Lewis acid such as Titanium alkoxides e.g. titanium tetraethoxide, titanium isopropoxide and the like, in ether solvents such as 1,4-dioxane, THF and like
  • the compound of formula (A3) reacted with reducing agent such as metal hydrides e.g. sodium borohydride, L-selectride and like, in solvents such as THF, 1,4- dioxane, methanol and the like, optionally in presence of water to provide sulfinamide of formula (A4).
  • reducing agent such as metal hydrides e.g. sodium borohydride, L-selectride and like
  • solvents such as THF, 1,4- dioxane, methanol and the like
  • Major diastereoisomer in the compound of formula (A4) after reduction was separated or taken ahead as such.
  • the compound of formula (A4) under acidic condition undergoes cleavage of reduced ketimine derivative to generate amine of formula (AS) as a free base or salt.
  • the acids employed for the transformation may involve mineral acids such as hydrochloric acid, organic acids like trifluoroacetic acid and thereof.
  • Compound of formula (B2) was converted to corresponding cyclic amide of formula (B3) through selective reduction of nitro group by using different reducing agents.
  • reducing agents include hydrogenation with palladium on carbon, metal reductions like iron, tin or tin chloride and the like.
  • Such reduction of the compound of formula (B2) can be carried out in one or more solvents, e.g., ethers such as THF, 1,4-dioxane, and the like; alcohol such as methanol, ethanol and the like; under acidic conditions involving ammonium chloride, acetic acid, hydrochloric acid and mixtures thereof.
  • solvents e.g., ethers such as THF, 1,4-dioxane, and the like
  • alcohol such as methanol, ethanol and the like
  • acidic conditions involving ammonium chloride, acetic acid, hydrochloric acid and mixtures thereof e.g., ethers such as THF, 1,4-dioxane, and the like
  • solvents e.g., ethers such as THF, 1,4-dioxane, and the like
  • alcohol such as methanol, ethanol and the like
  • ammonium chloride e.g., acetic acid, hydrochlor
  • Nitration of compound of formula (B3) with nitrating reagents such as, although not limited to fuming nitric acid, potassium nitrate, and the like in acids such as, although not limited to tin (TV) chloride, sulphuric acid, trifluroacetic acid, acetic acid and the like, anhydrides like acetic anhydride, trifluroacetic anhydride and the like, or mixture(s) thereof to provide compound of formula (B4).
  • Compound of formula (B4) can be further alkylated by using corresponding alkyl halide in presence of bases such as Na2CO3, K2CO3, CS2CO3 etc. in polar aprotic solvents like DMF, DMSO etc.
  • An alternative synthetic route towards the compound of formula (B5) is the transformation of intermediate of compound of formula (B4) via Mitsunobu reaction with corresponding alcohol, using different reagents such as but not limited to DEAD, DIAD etc.
  • Such reactions can be carried out in aprotic solvents like, e.g., ethers such as THF, Dioxane and the like; hydrocarbons, e.g., toluene or mixtures thereof, at temperature 25°C - 90°C.
  • Compound of formula (B5) was converted to corresponding aniline derivative compound of formula (B6) through selective reduction of nitro group by using different reducing agents.
  • such reducing agents include hydrogenation with palladium on carbon, metal reductions like iron, tin or tin chloride and the like.
  • reduction of the compound of formula (B5) can be carried out in one or more solvents, e.g., ethers such as THF, 1,4-dioxane, and the like; alcohol such as methanol, ethanol and the like; under acidic conditions involving ammonium chloride, acetic acid, hydrochloric acid and the like mixtures thereof.
  • Compound of formula (B6) upon treatment with corresponding alkylnitriles using acids such as but not limited to Methane sulfonic acid, HC1 etc.
  • compound of formula (B7) which could be further coupled with different chiral benzyl amine (A5) derivatives using diffaent coupling reagents such as but not limited to BOP, PyBop etc. and organic bases such as DBU, DIPEA etc. in a polar aprotic solvent like DMF, DMSO etc. at 0°-120°C to afford a compound of formula (I).
  • diffaent coupling reagents such as but not limited to BOP, PyBop etc. and organic bases such as DBU, DIPEA etc. in a polar aprotic solvent like DMF, DMSO etc. at 0°-120°C to afford a compound of formula (I).
  • compound of formula (I) can be prepared from compound of formula (B7) by reacting with phosporyl halides such as POCI 3 or POBr3 optionally in solvents such as toluene, xylene, chlorobenzene or the like or the mixtures thereof, optionally using organic base such as triethylamine, diisopropylethylamine or the like to provide compound of formula (B8).
  • phosporyl halides such as POCI 3 or POBr3
  • solvents such as toluene, xylene, chlorobenzene or the like or the mixtures thereof
  • organic base such as triethylamine, diisopropylethylamine or the like
  • Compound of formula (B8) undergoes a nucleophilic substitution reaction with different chiral benzylic amines (A5) leading to the final compound of formula (I) using organic basic reagents such as but not limited to DIPEA, TEA etc. optionally neat or in a polar aprotic solvents like dioxane, THF etc. at 0°C -130°C.
  • organic basic reagents such as but not limited to DIPEA, TEA etc. optionally neat or in a polar aprotic solvents like dioxane, THF etc. at 0°C -130°C.
  • Carbonyl functional group in Compound of formula (I) on further reduction using different reducing reagents such as but not limited to borane DMS, borane THF, LiA1H 4 in polar aprotic solvents like THF, dioxane etc. at temperature 70 - 90°C leading to final compound of formula (I).
  • Compound of formula (I) allowed to react with fluorinating reagent such as DAST, martin sulfurane in solvents such as DCM, chloroform, THF, ether, 1,4-dioxane to provide compound of formula (B9).
  • fluorinating reagent such as DAST, martin sulfurane in solvents such as DCM, chloroform, THF, ether, 1,4-dioxane
  • Compound of formula (B9) undergoes epoxidation reaction to provide compound of formula (BIO). This reaction is effected by hydrogen peroxide in presence of acidic medium using organic acids such as formic acid and like.
  • the compounds of formula (I) was prepared by following the sequential transformations as depicted and described in Scheme-C herein below-
  • Compound of formula (C2) is prepared by following a procedure reported in Chemistry - A European Journal, 2015, vol. 21, # 4, p. 1482 - 1487.
  • the compound of formula (C2) is converted to corresponding 4-oxo chromene carboxylic ester derivative of compound of formula (C3) using corresponding alpha diketo ester and basic reagents such as but not limited to NaOMe, NaOEt, KOBu etc. in a polar aprotic solvents like DMF, DMA etc. at 0°C - 75 °C.
  • Halogenation of compound of formula (C3) using N-halosuccinamide reagent such as but not limited to NBS , NIS and NCS gives corresponding dihalo compound of formula (C4) via e.g. benzylic halogenation in a aprotic halogenated solvents like CCl4, DCM etc. at 0°-80°C.
  • NBS N-halosuccinamide reagent
  • NCS NCS
  • Compound of formula (C5) undergoes an acidic hydrolysis leading to compound of formula (C6), that can be further functionalized to corresponding amide of compound of formula (C7) using coupling reagent such as but not limited to PyBop in a polar aprotic solvents like DMF, DMSO etc. at temperature ranging from 0°C -30°C for about l-16h.
  • Compound of formula (C8) can be achieved by oxidation of compound of formula (C7) with suitable oxidizing reagent such as but not limited to sulphamic acid and sodium chlorite.
  • Compound of formula (C8) when condensed with corresponding amidine by coupling reaction affords a quinazoline enone derivative of compound of formula (C9).
  • the compound of formula (CIO) can be transformed to the corresponding compound of formula (Cl 1) via halogenation using reagents such as phosphorus oxyhalide, thionyl chloride and like, in aprotic solvents like chlorobenzene, toluene and mixtures thereof.
  • Compound of formula (Cl 1) undergoes a coupling with different chiral benzylic amines (A5 ) leading to the final compound of formula (I).
  • This reaction can be effected by organic base such as DIPEA, TEA, DBU or the like, or using coupling reagents such as DCC, EDC, BOP, pyBOP, HBTU or the like; optionally neat or in etheral solvents such as THF, 1,4 dioxane and like or polar aprotic solvents like DMF, DMA, DMSO and thereof at temperature ranging from 20-130°C.
  • organic base such as DIPEA, TEA, DBU or the like
  • coupling reagents such as DCC, EDC, BOP, pyBOP, HBTU or the like
  • etheral solvents such as THF, 1,4 dioxane and like or polar aprotic solvents like DMF, DMA, DMSO and thereof at temperature ranging from 20-130°C.
  • the compound of formula (Dl) is converted to corresponding acetyl derivative of compound of formula (D2) via N-acylation reaction using acetyl chloride & using organic basic reagents such as but not limited to pyridine, DIPEA, TEA etc in halogenated solvents such as, although not limited chloroform, dichloromethane, and the like mixtures thereof.
  • organic basic reagents such as but not limited to pyridine, DIPEA, TEA etc in halogenated solvents such as, although not limited chloroform, dichloromethane, and the like mixtures thereof.
  • Nitration of compound of formula (D2) with nitrating reagents such as, although not limited to fuming nitric acid, potassium nitrate, and the like in acids such as, although not limited to tin (TV) chloride, sulphuric acid, trifluroacetic acid, acetic acid and the like, anhydrides like acetic anhydride, trifluroacetic anhydride and the like, or mixture(s) thereof to provide compound of formula (D3).
  • acids such as, although not limited to tin (TV) chloride, sulphuric acid, trifluroacetic acid, acetic acid and the like, anhydrides like acetic anhydride, trifluroacetic anhydride and the like, or mixture(s) thereof to provide compound of formula (D3).
  • compound of formula (D4) can be further alkylated by using alkyl halides and bases such as NaH, Na2CO3, K 2 CO 3 , Cs 2 CO 3 etc. in polar aprotic solvents like THF, DMF, and DMSO etc. at temperature 20°C - 60°C leading to compound of formula (D5).
  • Compound of formula (D5) can be converted to corresponding aniline derivative, compound of formula (D6) through selective reduction of nitro group by using different reducing agents.
  • such reducing agents include hydrogenation with palladium on carbon, metal reductions like iron, tin or tin chloride and the like.
  • Such reduction of the compound of formula (D6) can be carried out in one or more solvents, such as methanol, ethanol and the like; under acidic conditions involving ammonium chloride, acetic acid, hydrochloric acid and the like mixtures thereof.
  • Compound of formula (D6) allowed to react with alkylnitrile in presence of the acidic reagents such as methane sulfonic acid, sulfuric acid, hydrochloric acid or the like to obtain compound of formula (D7).
  • Compound of formula (D7) was reacted with POCI3 or POBr3 optionally in solvents such as toluene, xylene or the like or the mixtures thereof, optionally using organic base such as triethylamine, diisopropylethylamine or the like to provide compound of formula (D8).
  • Compound of formula (D8) was reacted with compound of formula (AS) in the presence DIPEA, TEA, DBU or the like, or using coupling reagents such as DCC, EDC, BOP, pyBOP, HBTU or the like; optionally neat or in etheral solvents such as THF, 1,4 dioxane and like or polar aptotic solvents like DMF, DMA, DMSO and thereof at temperature ranging from 20-130°C. to provide compound of formula (I).
  • coupling reagents such as DCC, EDC, BOP, pyBOP, HBTU or the like
  • etheral solvents such as THF, 1,4 dioxane and like or polar aptotic solvents like DMF, DMA, DMSO and thereof at temperature ranging from 20-130°C.
  • Compound of formula (E2) can be converted to corresponding cyclic amide of formula (E3) through selective reduction of nitro group by using different reducing agents.
  • reducing agents include hydrogenation with palladium on carbon, metal reductions like iron, tin or tin chloride and the like.
  • Such reduction of the compound of formula (E2) can be carried out in one or more solvents, alcohol such as methanol, ethanol and the like; under acidic conditions involving ammonium chloride, acetic acid, hydrochloric acid and the like mixtures thereof.
  • Compound of formula (E3) can be further alkylated by using bases such as NaH, Na 2 C0 3 , K2CO3, CS2CO3 etc.
  • Compound of formula (E5) can be synthesized by ester hydrolysis of compound of formula (E4) using bases such as NaOH, LiOH and KOH etc.
  • Compound of formula (E5) which on coupling with different amidines such as acetamidine, formamidine etc. in polar aprotic solvents like DMF, DMSO etc. at temperature 80°C - 100°C leading to compound of formula (E6).
  • Compound of formula (E6) can be converted to the corresponding compound of formula (E7) by halogenation using reagents such as POCI3, ⁇ 3, SOCI2 etc.
  • Compound of formula (E7) undergoes a nucleophilic substitution reaction with different chiral benzyl amine (AS) leading to compound of formula (I) using aprotic solvents like dioxane, THF and like, at temperature 0°C -130°C and bases such as but limited to DIPEA, TEA and thereof.
  • AS chiral benzyl amine
  • Compound of formula (F2) was converted to corresponding cychc amide of formula (F3) through selective reduction of nitro group by using different reducing agents.
  • reducing agents include hydrogenation with palladium on carbon, metal reductions like iron, tin or tin chloride and the like.
  • Such reduction of the compound of formula (F2) can be carried out in one or more solvents, such as methanol, ethanol and the like; under acidic conditions involving ammonium chloride, acetic acid, hydrochloric acid and the like mixtures thereof.
  • solvents such as methanol, ethanol and the like
  • Nitration of compound of formula (F3) with nitrating reagents such as, although not limited to fuming nitric acid, potassium nitrate, and the like in acids such as, although not limited to tin (IV) chloride, sulphuric acid, trifluroacetic acid, acetic acid and the like, anhydrides like acetic anhydride, trifluroacetic anhydride and the like, or mixture(s) thereof to provide compound of formula (F4).
  • Compound of formula (F4) can be treated with SOCl2 , POCI3, POBr3 and thereof using DMF to give an intermediate (Halogenation reaction intermediate), which undergoes a nucleophilic substitution reaction with appropriate amines leading to the compound of formula (F5), using organic basic reagents such as but not limited to DIPEA, TEA etc. in a polar aprotic solvent like dioxane, THF etc. at appropriate temperature.
  • organic basic reagents such as but not limited to DIPEA, TEA etc. in a polar aprotic solvent like dioxane, THF etc. at appropriate temperature.
  • Compound of formula (F5) can be converted to corresponding aniline derivative, compound of formula (F6) through selective reduction of nitro group by using different reducing agents.
  • reducing agents include hydrogenation with palladium on carbon, metal reductions like iron, tin or tin chloride and the like.
  • Such reduction of the compound of formula (F5) can be carried out in one or more solvents, such as methanol, ethanol and the like; under acidic conditions involving ammonium chloride, acetic acid, hydrochloric acid and mixtures thereof.
  • Compound of formula (F6) upon treatment with corresponding nitrile solvents such as but not limited to acetonitrile using acids such as but not limited to methane sulfonic acid, HC1 etc.
  • compound of formula (F7) which can be transformed to intermediate (F8), via e.g. triflate or halogenation etc. of the corresponding compound of formula (F7).
  • Compound of formula (F8) undergoes a nucleophilic substitution reaction with different chiral benzyl amine (A5), using aprotic solvents like dioxane, THF etc., at temperature 0°C-130°C and bases such as but limited to DIPEA, TEA etc. leading to final compound of formula (I).
  • suitable base preferably inorganic bases such as alkali metal carbonates, e.g., Na2CO3, K2CO3, CS2CO3, NaO3 ⁇ 4u, Potassium phosphate, or mixture thereof.
  • suitable base preferably inorganic bases such as alkali metal carbonates, e.g., Na2CO3, K2CO3, CS2CO3, NaO3 ⁇ 4u, Potassium phosphate, or mixture thereof.
  • suitable base preferably inorganic bases such as alkali metal carbonates, e.g., Na2CO3, K2CO3, CS2CO3, NaO3 ⁇ 4u, Potassium phosphate, or mixture thereof.
  • solvents like, e.
  • Nitration of compound of formula (G3) with nitrating reagents such as, although not limited to fuming nitric acid, potassium nitrate, and the like in acids such as, although not limited to tin (IV) chloride, sulphuric acid, trifluroacetic acid, acetic acid and the like, anhydrides like acetic anhydride, trifluroacetic anhydride and the like, or mixture(s) thereof to provide compound of formula (G4).
  • the compound of formula (G4) was alkylated to give compound of formula (G5).
  • This conversion was effected in presence alkali hydrides like sodium hydride and like; or bases such as potassium carbonate and like; and alkylating reagents alkyl halides e.g. Methyl iodide and like; in presence of solvents such as THF, DMF or mixture(s) thereof.
  • Compound of the formula (G6) was obtained from compound of formula (G5) using by metal reductions using iron, tin or tin chloride or the like in solvents selected from THF, 1,4-dioxane methanol, ethanol or the like or mixtures thereof under acidic condition using ammonium chloride, acetic acid, hydrochloric acid or the like or mixture(s) thereof.
  • This transformation can also be carried out by catalytic hydrogenation using Pd/C and thereof in solvents ethyl acetate, Methanol or mixture(s) thereof.
  • Compound of formula (HI) can be synthesized by reaction protocol as mentioned in (W0243823).
  • Compound of formula (H2) can be synthesized from compound of formula (HI) by using oxidizing agents like MnO2, H2O2, AgNOa, DDQ and thereof.
  • Compound of formula (H2) undergoes alkylation reaction using alkyl halides in presence of bases such as K2CO3, Na 2 C0 3 , CS2CO3 and like; in polar aprotic solvents like DMF, DMSO and thereof; at temperature 20°C - 60°C afforded compound of formula (H3).
  • An alternative synthetic route towards the compound of formula (H3) is the transformation of intermediate of compound of formula (H2) via Mitsunobu reaction with corresponding alcohol, using different reagents such as but not limited to DEAD, DIAD etc.
  • Such reactions can be carried out in aprotic solvents like, e.g., ethos such as THF, Dioxane and the like; hydrocarbons, e.g., toluene or mixtures thereof, at temperature 25°C - 90°C.
  • aprotic solvents like, e.g., ethos such as THF, Dioxane and the like; hydrocarbons, e.g., toluene or mixtures thereof, at temperature 25°C - 90°C.
  • Compound of formula (H4) can be synthesized by ester hydrolysis of formula (H3) using bases such as NaOH, LiOH, KOH and like; in polar protic solvents such as methanol, ethanol and like.
  • the compound of the formula (12) obtained by treating compound of the formula (II) with oxidizing agent potassium permanganate, potassium dichromate, sodium dichromate in presence of acids like sulphuric acid, acetic acid and like, in 1:1 mixture of t-butanol and Water as Solvent.
  • the compound of formula (12) was subjected to esterification in alcoholic solvents like methanol ethanol and thereof in presence of chlorinating agents such as thionyl chloride, oxalyl chloride and thereof, or in presence of acidic reagents such as sulfuric and methane sulfonic acid thereof to provide the compound of formula (13).
  • the compound of formula (13) was subjected to C-N coupling reaction e.g. Buchwald reaction with 1- methylurea provided compound of formula (14).
  • This reaction can mediated by a suitable catalyst such as, e.g., Pd(PPh3)2Cl2, Pd2dba3, Pd(PPh3)4, Pd(OAc)2 or mixtures thereof; a suitable ligand such as Xantphos, BINAP, Ru-Phos, XPhos, or mixtures thereof; in the presence of suitable base, preferably inorganic bases such as alkali metal carbonates, e.g., K2CO3, Na2CO3, CS2CO3, NaOtBu, Potassium phosphate, or mixture thereof.
  • a suitable catalyst such as, e.g., Pd(PPh3)2Cl2, Pd2dba3, Pd(PPh3)4, Pd(OAc)2 or mixtures thereof
  • a suitable ligand such as Xantphos, BINAP, Ru-Phos, XPhos, or mixtures thereof
  • suitable base preferably inorganic bases such as alkali metal carbonates, e.g.,
  • Such reactions can be carried out in solvents like, e.g., ethers such as THF, Dioxane and the like; hydrocarbons, e.g., toluene; amides such as DMF, DMA or mixtures thereof.
  • solvents like, e.g., ethers such as THF, Dioxane and the like; hydrocarbons, e.g., toluene; amides such as DMF, DMA or mixtures thereof.
  • Nitration of compound of formula (14) with nitrating reagents such as, although not limited to fuming nitric acid, potassium nitrate, and the like in acids such as, although not limited to tin (IV) chloride, sulphuric acid, trifluroacetic acid, acetic acid and the like, anhydrides like acetic anhydride, trifluroacetic anhydride and the like, or mixture(s) thereof to provide compound of formula (15).
  • the compound of formula (15) was alkylated to give compound of formula (16). This conversion was effected in presence alkali hydrides like sodium hydride and like; or bases such as potassium carbonate and like; and alkylating reagents alkyl halides e.g. Methyl iodide and like; in presence of solvents such as THF, DMF or mixture(s) thereof.
  • alkali hydrides like sodium hydride and like
  • bases such as potassium carbonate and like
  • alkylating reagents alkyl halides e.g. Methyl iodide and like
  • solvents such as THF, DMF or mixture(s) thereof.
  • Compound of the formula (17) was obtained from compound of formula (16) using by metal reductions using iron, tin or tin chloride or the like in solvents selected from THF, 1,4-dioxane methanol, ethanol or the like or mixtures thereof under acidic condition using ammonium chloride, acetic acid, hydrochloric acid or the like or mixture(s) thereof.
  • This transformation can also be carried out by catalytic hydrogenation using Pd/C and thereof in solvents ethyl acetate, Methanol or mixture(s) thereof.
  • Such reaction can be carried out by using Lewis acids such as, although not limited to AlC3, BF3, etc., either neat or by using solvents such as DCM, DCE, chlrobenzene, toluene, xylene, etc. and the like or mixture(s) thereof.
  • Nitration of compound of formula (J3) with nitrating reagents such as, although not limited to fuming nitric acid, potassium nitrate, and the like in acids such as, although not limited to tin (TV) chloride, sulphuric acid, trifluroacetic acid, acetic acid and the like, anhydrides like acetic anhydride, trifluroacetic anhydride and the like, or mixture(s) thereof to provide compound of formula (J4).
  • Compound of formula (J4) can be further alkylated by using bases such as NaH, K2CO3, Na2CO3, CS2CO3 etc. in polar aprotic solvents like THF, DMF, DMSO etc.
  • compound of formula (J5) was converted to corresponding aniline derivative compound of formula (J6) through selective reduction of nitro group by using different reducing agents.
  • reducing agents include hydrogenation with palladium on carbon, metal reductions like iron, tin or tin chloride and the like.
  • reduction can be carried out in one or more solvents, e.g., ethers such as THF, 1,4-dioxane, and the like; alcohol such as methanol, ethanol and the like; under acidic conditions involving ammonium chloride, acetic acid, hydrochloric acid and the like mixtures thereof.
  • This reaction can also be caned out by using combination of halogenating reagents and organic bases such as POCh, POBr3, SOCI2 and the like; and organic bases like DIPEA, TEA, ⁇ , ⁇ -Dimethylaniline and the like; using solvents such as DCE, DCM, chlorobenzene, toluene and the like or mixture(s) thereof at appropriate temperature.
  • organic bases such as POCh, POBr3, SOCI2 and the like
  • organic bases like DIPEA, TEA, ⁇ , ⁇ -Dimethylaniline and the like
  • solvents such as DCE, DCM, chlorobenzene, toluene and the like or mixture(s) thereof at appropriate temperature.
  • the compound of formula (I) can be obtained by using nucleophilic substitution of benzyl amines (A5) with the compound of the formula (J8).
  • Such reaction can be carried out at appropriate temperature in presence of bases like DIPEA, TEA and the like; in solvents such as THF, 1,4-Dioxane, DCE, ACN, DMSO, etc., and the like or mixture(s) thereof.
  • bases like DIPEA, TEA and the like
  • solvents such as THF, 1,4-Dioxane, DCE, ACN, DMSO, etc., and the like or mixture(s) thereof.
  • the compound of formula (Kl) was subjected to esterification in alcoholic solvents like methanol ethanol and thereof in presence of chlorinating agents such as thionyl chloride, oxalyl chloride and thereof, or in presence of acidic reagents such as sulfuric and methane sulfonic acid thereof to provide the compound of formula (K2).
  • Compound of formula (K3) can be synthesized by appropriate displacement of aromatic halogen with corresponding alkyl amine in alcoholic solvents like methanol ethanol and thereof.
  • the compound of formula (K5) was alkylated to give compound of formula (K6).
  • This conversion was effected in presence alkali hydrides like sodium hydride and like; or bases such as potassium carbonate and like; and alkylating reagents alkyl halides e.g. Methyl iodide and like; in presence of solvents such as THF, DMF or mixture(s) thereof.
  • the compound of formula (K6) was subjected to C-N coupling reaction e.g. Buchwald reaction with tert-butyl carbamate provided compound of formula (K7).
  • This reaction can mediated by a suitable catalyst such as, e.g., Pd(PPh3)2Cl2, Pd2dba3, Pd(PPh3)4, Pd(OAc)2 or mixtures thereof; a suitable ligand such as Xantphos, BINAP, Ru-Phos, XPhos, or mixtures thereof; in the presence of suitable base, preferably inorganic bases such as alkali metal carbonates, e.g., K2CO3, Na2CO3, CS2CO3, NaOtBu, Potassium phosphate, or mixture thereof.
  • a suitable catalyst such as, e.g., Pd(PPh3)2Cl2, Pd2dba3, Pd(PPh3)4, Pd(OAc)2 or mixtures thereof
  • a suitable ligand such as X
  • Such reactions can be carried out in solvents like, e.g., ethers such as THF, Dioxane and the like; hydrocarbons, e.g., toluene; amides such as DMF, DMA or mixtures thereof.
  • Compound of formula (K7) undergoes deprotection using acids like organic acids such as trifluoroacetic acid, Methane sulfonic acid and like, mineral acids like hydrochloric acid, acetic acid (Aqueous or in etheral solvents), sulfuric acid and the like; using solvents like dichloromethane, dichloroethane, THF, 1,4-dioxane and like thereof to provide compound of formula (K8).
  • Nitration of compound of formula (L2) with nitrating reagents such as, although not limited to fuming nitric acid, potassium nitrate, and the like in acids such as, although not limited to tin (TV) chloride, sulphuric acid, trifluroacetic acid, acetic acid and the like, anhydrides like acetic anhydride, trifluroacetic anhydride and the like, or mixture(s) thereof to provide compound of formula (L3).
  • Compound of formula (L3) was converted to corresponding aniline derivative compound of formula (L4) through selective reduction of nitro group by using different reducing agents.
  • such reducing agents include hydrogenation with palladium on carbon, metal reductions like iron, tin or tin chloride and the like.
  • reduction of the compound of formula (L3) can be carried out in one or more solvents, e.g., ethers such as THF, 1,4-dioxane, and the like; alcohol such as methanol, ethanol and the like; under acidic conditions involving ammonium chloride, acetic acid, hydrochloric acid and the like mixtures thereof.
  • Compound of formula (L4) allowed to react with corresponding acyl halide in presence of the organic basic reagents such as but not limited to DIPEA, TEA etc. in polar aprotic solvents like DMF, DMSO etc.
  • Compound of formula (L5) can be further alkylated by using bases such as K2CO3, Na 2 C0 3 , CS2CO3 etc. in polar aprotic solvents like DMF, DMSO etc. at temperature 20°C - 60°C leading to compound of formula (L6).
  • Compound of formula (L6) which on coupling with different amidines such as acetamidine, formamidine etc. in polar aprotic solvents like DMF, DMSO etc. at temperature 80°C - 100°C leading to compound of formula (L7).
  • Compound of formula (L8) can be prepared from compound of formula (L7) by reacting with phosporyl halides such as POCI3 or ⁇ 3 optionally in solvents such as toluene, xylene, chlorobenzene or the like or the mixtures thereof, optionally using organic base such as triethylamine, diisopropylethylamine or the like to provide compound of formula (L8).
  • phosporyl halides such as POCI3 or ⁇ 3
  • solvents such as toluene, xylene, chlorobenzene or the like or the mixtures thereof
  • organic base such as triethylamine, diisopropylethylamine or the like
  • Compound of formula (L8) undergoes a nucleophilic substitution reaction with different chiral benzylic amines (A5) leading to the final compound of formula (I) using organic basic reagents such as but not limited to DIPEA, TEA etc. in a polar aptotic solvents like dioxane, THF etc. at 0°C -130°C.
  • organic basic reagents such as but not limited to DIPEA, TEA etc. in a polar aptotic solvents like dioxane, THF etc. at 0°C -130°C.
  • Carbonyl functional group in Compound of formula (Ml) on further reduction using different reducing reagents such as but not limited to triethyl silane, borane DMS, borane THF, LLA1H4 in polar aptotic solvents like THF, dioxane etc or like in acids such as, although not limited to trifluroacetic acid, sulphuric acid, acetic acid and the like, or mixture(s) thereof to provide compound of formula (M2).
  • Compound of formula (M6) can be prepared from compound of formula (M5) by reacting with phosporyl halides such as POCI3 or POBr3 optionally in solvents such as toluene, xylene, chlorobenzene or the like or the mixtures thereof, optionally using organic base such as triethylamine, diisopropylethylamine or the like to provide compound of formula (M6).
  • phosporyl halides such as POCI3 or POBr3 optionally in solvents such as toluene, xylene, chlorobenzene or the like or the mixtures thereof, optionally using organic base such as triethylamine, diisopropylethylamine or the like to provide compound of formula (M6).
  • Compound of formula (M6) undergoes a nucleophilic substitution reaction with different chiral benzylic amines (A5) leading to the final compound of formula (I) using organic basic reagents such as but not limited to DIPEA
  • the compounds of formula (I) was prepared by following the sequential transformations as depicted and described in Scheme - N herein below.
  • Compound of the formula (N2) was obtained by oxidation of compound of the formula (Nl). This transformation can be effected by oxidizing reagents such as potassium permanganate, potassium dichromate, sodium dichromate and like; in presence of acids like H2SO4, acetic acid and like.
  • Compound of the formula (N3) was obtained from compound of the formula (N2) by esterification reaction.
  • This transformation can be effected by reaction of alcohols such as methanol, ethanol and like; in presence of mineral acids like sulfuric acid, organic acids like methane sulfonic acid and like, or in presence of chloride reagents like thionyl chloride, oxalyl chloride and thereof.
  • This transformation can also be effected by Mitsonobu reaction between acid (N3) and corresponding alcohols in presence of Triaryl phosphines and azo carboxylates such as DEAD, DIAD and like.
  • Compound of formula (N6) undergoes N-alkylation using alkyl halides and bases such as K2CO3, Na2CO3, CS2CO3; organic bases like diisopropylethyl amine, DBU, DAB CO and so on; in polar aprotic solvents like DMF, DMSO, acetone and like, etheral solvents such as THF, 1, 4-dioxane and like, at room temperature or elevated temperatures provide compound of formula (N7).
  • alkyl halides and bases such as K2CO3, Na2CO3, CS2CO3
  • organic bases like diisopropylethyl amine, DBU, DAB CO and so on
  • polar aprotic solvents like DMF, DMSO, acetone and like
  • etheral solvents such as THF, 1, 4-dioxane and like
  • Compound of formula (N8) undergoes deprotection using acids like organic acids such as trifluoroacetic acid, Methane sulfonic acid and like, mineral acids like hydrochloric acid, acetic acid (aqueous or in etheral solvents), sulfuric acid and the like; using solvents like dichloromethane, dichloroethane, THF, 1,4-dioxane and like thereof to provide compound of formula (N9).
  • acids like organic acids such as trifluoroacetic acid, Methane sulfonic acid and like, mineral acids like hydrochloric acid, acetic acid (aqueous or in etheral solvents), sulfuric acid and the like
  • solvents like dichloromethane, dichloroethane, THF, 1,4-dioxane and like thereof to provide compound of formula (N9).
  • compound of formula (N8) on reaction with alkylnitrile in presence of the acidic reagents such as methane sulfonic acid, sulfuric acid, hydrochloric acid or the like can directly give compound of formula (N10)
  • compound of formula (N10) can also be obtained directly from compound of formula (N8) by reaction alkylnitrile in presence of the acidic reagents such as methane sulfonic acid, sulfuric acid, hydrochloric acid and thereof.
  • Compound of formula (Nil) allowed to react with compound of formula (A5) in presence of suitable coupling reagent to provide compound of formula (N12).
  • the reaction can be carried out in presence of organic base such as diisopropylethylamine, triethylamine, DBU or the like, or using coupling reagents such as DCC, EDC, BOP, pyBOP, HBTU or the like; in etheral solvents such as THF, 1 ,4 dioxane and like or polar aprotic solvents like DMF, DMA, DMSO and thereof.
  • organic base such as diisopropylethylamine, triethylamine, DBU or the like
  • coupling reagents such as DCC, EDC, BOP, pyBOP, HBTU or the like
  • etheral solvents such as THF, 1 ,4 dioxane and like or polar aprotic solvents like DMF, DMA, DMSO and
  • Compound of formula (N14) undergoes C-alkylation reaction with alkyl halides in presence of bases such as NaH, sodium/potassium alkoxides, K2CO3, Na2CO3, CS2CO3; organic bases like diisopropylethyl amine, DBU, DABCO and so on; in polar aprotic solvents like DMF, DMSO, acetone and like, etheral solvents such as THF, 1, 4-dioxane and like, at room temperature or elevated temperatures provide compound of formula (N15) Compound of formula (N15) can be converted to compound of formula (I) in five steps by employing analogous protocol mentioned above in scheme -N for the conversion of compound of formula (N7) to compound of formula (N12).
  • bases such as NaH, sodium/potassium alkoxides, K2CO3, Na2CO3, CS2CO3
  • organic bases like diisopropylethyl amine, DBU, DABCO and so on
  • the compound of formula (01) undergoes alkylation/acylation reaction to give compound of formula (Oil) the reaction was carried out using alkyl halides/ acyl halide and bases like Lithium diisopropylamide, butyl lithium, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, sodium tert-butoxide, potassium tertbutoxide, sodium ethoxide, sodium methoxide, cesium carbonate, potassium carbonate or the like possibly in the presence of additives such as N,N,N',N'-Tetramethylethane-1, 2-diamine in solvents selected from THF, 1,4-dioxane, DMF and like
  • Compound of formula (013) undergoes esterification reaction to corresponding compound of formula (05) using solvents such as methanol, ethanol, propanol, tert-butanol using acidic conditions like hydrochloric acid, sulfuric acid, thionyl chloride or the like or mixture(s) thereof.
  • solvents such as methanol, ethanol, propanol, tert-butanol using acidic conditions like hydrochloric acid, sulfuric acid, thionyl chloride or the like or mixture(s) thereof.
  • Compound of formula (07) undergoes deprotection using acids like organic acids such as trifluoroacetic acid, Methane sulfonic acid and like, mineral acids like hydrochloric acid, acetic acid (aqueous or in etheral solvents), sulfuric acid and the like; using solvents like dichloromethane, dichloroethane, THF, 1,4-dioxane and like, to provide compound of formula (08).
  • acids like organic acids such as trifluoroacetic acid, Methane sulfonic acid and like, mineral acids like hydrochloric acid, acetic acid (aqueous or in etheral solvents), sulfuric acid and the like; using solvents like dichloromethane, dichloroethane, THF, 1,4-dioxane and like, to provide compound of formula (08).
  • compound of formula (07) on reaction with alkylnitrile in presence of the acidic reagents such as methane sulfonic acid, sulfuric acid, hydrochloric acid or the like can directly give compound of formula (09)
  • phosporyl halides such as POCI3 or POBrg
  • organic base such as triethylamine, diisopropylethylamine or the like
  • the reaction can be carried out in presence of organic base such as diisopropylethylamine, triethylamine, DBU or the like, or using coupling reagents such as DCC, EDC, BOP, pyBOP, HBTU or the like; in etheral solvents such as THF, 1,4 dioxane and like or polar aprotic solvents like DMF, DMA, DMSO and thereof.
  • organic base such as diisopropylethylamine, triethylamine, DBU or the like
  • coupling reagents such as DCC, EDC, BOP, pyBOP, HBTU or the like
  • etheral solvents such as THF, 1,4 dioxane and like or polar aprotic solvents like DMF, DMA, DMSO and thereof.
  • compound of formula (OIO) converted to compound of formula (014) using halogenating reagents such as NBS, NCS, bromine and like, in polar solvents such as DMF, AcOH, DCM and like.
  • Compound of formula (015) was prepared from compound of formula (014) using C-C coupling reactions such as Suzuki coupling reaction using corresponding boronic acid in presence of Pd catalyst such as tris(dibenzylideneacetone) dipalladium(O), palladium(II)acetate, Bis(dibenzylideneacetone)2Pd(0), rac 2,2'- B is(diphenylphosphino)- 1 , 1 '-binaphthyl, 2,5 bis(tri-t-butylphosphine) palladium (0), Pd(PPh3)4 and like in base such as K2CO3, Na2CO3, CS2CO3, Potassium phosphate and like; in solvents such as toluene, 1,4-d
  • the compound of formula (014) can be converted to compound of formula (I) using similar protocol used earlier for conversion of compound of formula (09) to compound of formula (I) in two steps.
  • Compound of the formula (P2) was obtained by oxidation of compound of the formula (PI). This transformation can be effected by oxidizing reagents such as potassium permanganate, potassium dichromate, sodium dichromate and like; in presence of acids like H2SO4, acetic acid and like.
  • oxidizing reagents such as potassium permanganate, potassium dichromate, sodium dichromate and like; in presence of acids like H2SO4, acetic acid and like.
  • Compound of formula (P2) undergoes N-alkylation using alkyl halides in presence of bases such as NaH, Potassium/sodium alkoxides, K2CO3, Na2CO3, CS2CO3 .organic bases like diisopropylethyl amine, DBU, DABCO and so on; in polar aprotic solvents like DMF, DMSO, acetone and like, etheral solvents such as THF, 1,4-dioxane and like, at room temperature or elevated temperatures provide compound of formula (P3).
  • bases such as NaH, Potassium/sodium alkoxides, K2CO3, Na2CO3, CS2CO3 .
  • organic bases like diisopropylethyl amine, DBU, DABCO and so on
  • polar aprotic solvents like DMF, DMSO, acetone and like
  • etheral solvents such as THF, 1,4-dioxane and like
  • Compound of formula (P3) undergoes reaction with organometallic reagents such as grignard reagent, dialkyl zinc , alkyl lithiums, and thereof; silane reagents such as trifluromethyl trimethyl silane and thereof; in etheral solvents such as THF, MTBE and like to provide compounds of formula (P4)
  • organometallic reagents such as grignard reagent, dialkyl zinc , alkyl lithiums, and thereof
  • silane reagents such as trifluromethyl trimethyl silane and thereof
  • etheral solvents such as THF, MTBE and like
  • Compound of formula (P4) undergoes O-alkylation using alkyl halides in presence of bases such as sodium hydride, potassium /sodium alkoxide K2CO3, Na2CO3, CS2CO3, NaH and thereof; organic bases like diisopropylethyl amine, DBU, DAB CO and so on; in polar apro
  • Compound of formula (P5) allowed to react with tert-butyl carbamate in the presence of catalyst such as (tris(dibenzylideneacetone) dipalladium(O), palladium ( ⁇ ) acetate, Bis(dibenzylideneacetone)2 Pd(0), racemic 2,2'-Bis(diphenylphosphino)-l,l'-binaphthyl, 2,5 bis(tri-t-butylphosphine) palladium (0) and the like; in presence of ligands such as RuPhos, Xanthphos, Davephos, BINAP, or the like; using a suitable base such as sodium carbonate, cesium carbonate, sodium tert-butoxide, potassium tert-butoxide, DIPEA, Potassium triphosphate and thereof; in a suitable solvent selected from THF, 1,4-dioxane, dimethoxyethane, DMF, DMA, toluene and
  • Compound of formula (P9) undergoes deprotection using acids like organic acids such as trifluoroacetic acid, Methane sulfonic acid and like, mineral acids like hydrochloric acid, acetic acid (aqueous or in etheral solvents), sulfuric acid and the like; using solvents like dichloromethane, dichloroethane, THF, 1,4-dioxane and like thereof to provide compound of formula (P10).
  • acids like organic acids such as trifluoroacetic acid, Methane sulfonic acid and like, mineral acids like hydrochloric acid, acetic acid (aqueous or in etheral solvents), sulfuric acid and the like
  • solvents like dichloromethane, dichloroethane, THF, 1,4-dioxane and like thereof to provide compound of formula (P10).
  • compound of formula (P9) on reaction with alkylnitrile in presence of the acidic reagents such as methane sulfonic acid, sulfuric acid, hydrochloric acid or the like can directly give compound of formula
  • Compound of formula (P7) allowed to react with phosporyl halides such as POCI3 or POBrg optionally in solvents such as toluene, xylene, chlorobenzene or the like or the mixtures thereof, optionally using organic base such as triethylamine, diisopropylethylamine or the like to provide compound of formula (P8).
  • Compound of formula (P8) allowed to react with compound of formula (A5) in presence of suitable coupling reagent to provide compound of formula (I).
  • the reaction can be carried out in presence of organic base such as diisopropylethylamine, triethylamine, DBU or the like, or using coupling reagents such as DCC, EDC, BOP, pyBOP, HBTU or the like; in etheral solvents such as THF, 1,4 dioxane and like or polar aprotic solvents like DMF, DMA, DMSO and thereof.
  • organic base such as diisopropylethylamine, triethylamine, DBU or the like
  • coupling reagents such as DCC, EDC, BOP, pyBOP, HBTU or the like
  • etheral solvents such as THF, 1,4 dioxane and like or polar aprotic solvents like DMF, DMA, DMSO and thereof.
  • the compounds of formula (I) was prepared by following the sequential transformations as depicted and described in Scheme-Q herein below
  • This type of transformations can be carried out at appropriate temperature using alkali bases such as NaOH, KOH and like; carbonates such as potassium carbonate, cesium carbonate and like; or organic bases like Triethylamine, diisopropyl ethyl amine and the like; in amidic solvents like DMF, DMA and like; etheral solvents like 1, 4-dioxane, THF and mixtures thereof.
  • Compound of formula (Q2) undergoes decarboxylation reaction to furnish compound of formula (Q3).
  • This transformation was carried out in polar solvents like DMSO, DMF, and like, using sodium chloride, lithium chloride and like. Similar transformation can be done using acids such as sulfuric acid, trifluoroacetic acid and like, at appropriate temperature.
  • Reductive cyclization of compound of the formula (Q3) provide compound of formula (Q4).
  • the reduction of nitro group was carried out using different reagents; although not limited, such reducing agents include hydrogenation with palladium on carbon, metal reductions like iron, tin or tin chloride and the like.
  • reaction are carried out in one or more solvents, e.g., ethers such as THF, 1, 4-dioxane, and the like; alcohol such as methanol, ethanol and the like; under acidic conditions involving ammonium chloride, acetic acid, hydrochloric acid and the like mixtures thereof.
  • solvents e.g., ethers such as THF, 1, 4-dioxane, and the like; alcohol such as methanol, ethanol and the like; under acidic conditions involving ammonium chloride, acetic acid, hydrochloric acid and the like mixtures thereof.
  • Compound of formula (Q4) undergoes alkylation reaction by reacting with corresponding alkyl halide in presence of bases such as sodium hydride, potassium tert butoxide, K2CO3, Na2CO3, CS2CO3; organic bases like diisopropyl ethyl amine, DBU, DAB CO and the like; in polar aprotic solvents like DMF, DMSO, acetone and like, etheral solvents such as THF, 1, 4-dioxane and like, at appropriate temperature provided compound of formula (Q5).
  • bases such as sodium hydride, potassium tert butoxide, K2CO3, Na2CO3, CS2CO3
  • organic bases like diisopropyl ethyl amine, DBU, DAB CO and the like
  • polar aprotic solvents like DMF, DMSO, acetone and like
  • etheral solvents such as THF, 1, 4-dioxane and like
  • Compound of formula (Q3) undergoes C-alkylation reaction by reacting with corresponding alkyl halide in presence of bases such as sodium hydride, potassium tert butoxide and like; in polar aprotic solvents like DMF, DMSO, acetone and like, etheral solvents such as THF, 1, 4-dioxane and like, to provide compound of formula (Qll).
  • bases such as sodium hydride, potassium tert butoxide and like
  • polar aprotic solvents like DMF, DMSO, acetone and like, etheral solvents such as THF, 1, 4-dioxane and like
  • Compound of formula (Q12) undergoes N-alkylation reaction with alkyl halides in presence of bases such as NaH, Potassium/sodium alkoxides, K2CO3, Na2CO3, CS2CO3.organic bases like diisopropylethyl amine, DBU, DABCO and so on; in polar aprotic solvents like DMF, DMSO, acetone and like, etheral solvents such as THF, 1, 4-dioxane and like, at room temperature or elevated temperatures provide compound of formula (Q5)
  • Compound of formula (Q2) undergoes C-alkylation using corresponding alkyl halide in presence of bases such as sodium hydride, potassium tert butoxide , K 2 CO 3 , Na2CO3, CS 2 CO 3 and like; in polar aprotic solvents like DMF, DMSO, acetone and like, etheral solvents such as THF, 1, 4-dioxane and like to provide compound of formula
  • Compound of formula (Q6) undergoes deprotection using acids like organic acids such as trifluoroacetic acid, Methane sulfonic acid and like, mineral acids like hydrochloric acid, acetic acid (Aqueous or in etheral solvents), sulfuric acid and the like; using solvents like dichloromethane, dichloroethane, THF, 1,4-dioxane and like thoeof to provide compound of formula (Q7).
  • acids like organic acids such as trifluoroacetic acid, Methane sulfonic acid and like, mineral acids like hydrochloric acid, acetic acid (Aqueous or in etheral solvents), sulfuric acid and the like.
  • solvents like dichloromethane, dichloroethane, THF, 1,4-dioxane and like thoeof to provide compound of formula (Q7).
  • compound of formula (Q6) on reaction with alkylnitrile in presence of the acidic reagents such as methane sulfonic acid, sulfuric acid, hydrochloric acid or the like can directly give compound of formula
  • Compound of formula (Q8) allowed to react with phosporyl halides such as POCI3 or POBrg optionally in solvents such as toluene, xylene, chlorobenzene or the like or the mixtures thereof, optionally using organic base such as triethylamine, diisopropylethylamine or the like to provide compound of formula (Q9).
  • Compound of formula (Q9) allowed to react with compound of formula (A5) in presence of suitable coupling reagent to provide compound of formula (I).
  • the reaction can be carried out in presence of organic base such as diisopropylethylamine, triethylamine, DBU or the like, or using coupling reagents such as DCC, EDC, BOP, pyBOP, HBTU or the like; in etheral solvents such as THF, 1,4 dioxane and like or polar aprotic solvents like DMF, DMA, DMSO and thereof.
  • organic base such as diisopropylethylamine, triethylamine, DBU or the like
  • coupling reagents such as DCC, EDC, BOP, pyBOP, HBTU or the like
  • etheral solvents such as THF, 1,4 dioxane and like or polar aprotic solvents like DMF, DMA, DMSO and thereof.
  • Compound of formula (Q17) undergoes displacement reaction with primary or secondary amines in presence of alcohol solvents such as ethanol, IPA and mixtures thereof to provide compound of formula (I).
  • Compound of formula (Q10) undergoes epoxidation reaction to provide compound of formula (Q18). This reaction is effected by hydrogen peroxide in presence of acidic medium using organic acids such as formic acid and like.
  • Compound of formula (R3) undergoes alkylation using alkyl halides in presence of bases such as sodium hydride, potassium /sodium alkoxide bases such as K2CO 3 , Na2CC3, CS2CO 3 ; organic bases like diisopropylethyl amine, DBU, DABCO and so on; in polar aprotic solvents like DMF, DMSO and like, at room temperature or elevated temperatures provide compound of formula (R4).
  • bases such as sodium hydride, potassium /sodium alkoxide bases such as K2CO 3 , Na2CC3, CS2CO 3 ; organic bases like diisopropylethyl amine, DBU, DABCO and so on; in polar aprotic solvents like DMF, DMSO and like, at room temperature or elevated temperatures provide compound of formula (R4).
  • Compound of formula (R5) undergo reductive cyclization to provide compound of formula (R6).
  • This nitro reduction can be achieved by reducing agents include hydrogenation with palladium on carbon, metal reductions like iron, tin or tin chloride and the like.
  • reducing agents include hydrogenation with palladium on carbon, metal reductions like iron, tin or tin chloride and the like.
  • These reactions are carried out in one or more solvents, e.g., ethers such as THF, 1,4-dioxane, and the like; alcohol such as methanol, ethanol and the like; under acidic conditions involving ammonium chloride, acetic acid, hydrochloric acid and the like mixtures thereof.
  • Compound of formula (R6) undergoes N-alkylation using alkyl halides in presence of bases such as sodium hydride, potassium /sodium alkoxide bases such as K2CO3, Na2CO3, CS2CO3; organic bases like diisopropylethyl amine, DBU, DABCO and so on; in polar aprotic solvents like DMF, DMSO and like, at room temperature or elevated temperatures provide compound of formula (R7).
  • bases such as sodium hydride, potassium /sodium alkoxide bases such as K2CO3, Na2CO3, CS2CO3
  • organic bases like diisopropylethyl amine, DBU, DABCO and so on
  • polar aprotic solvents like DMF, DMSO and like
  • Compound of formula (R7) can be converted to the compound of formula (Rll) by employing 4 step protocol mentioned in conversion of compound of formula (N8) to compound of formula (N12)
  • Compound of formula (Rll) undergoes decarboxylation reaction to furnish compound of the formula (R12).
  • This transformation can be effected by acidic reagents such as mineral acids like sulfuric acid, organic acids like trifluoroacetic acid and thereof; similar transformation can be achieved using sodium chloride, lithium chloride and thereof, in solvents such as dimethyl sulfoxide and like; at elevated temperatures.
  • Compound of formula (R12) converted to compound of formula (I) using ceric ammonium nitrate, thallium nitrate and thereof in present of alcoholic solvents like methanol, ethanol and thereof.
  • Compound of formula (R14) undergoes coupling reaction with compound of formula (A5) to furnish compound of formula (I).
  • the reaction can be carried out in presence of organic base such as diisopropylethylamine, triethylamine, DBU or the like, or using coupling reagents such as DCC, EDC, BOP, pyBOP, HBTU or the like; either neat reaction in base or in etheral solvents such as THF, 1,4 dioxane and like or polar aprotic solvents like DMF, DMA, DMSO and thereof.
  • organic base such as diisopropylethylamine, triethylamine, DBU or the like
  • coupling reagents such as DCC, EDC, BOP, pyBOP, HBTU or the like
  • THF 1,4 dioxane and like
  • polar aprotic solvents like DMF, DMA, DMSO and thereof.
  • Compound of formula (R15) undergoes fluorination reaction by fluorinating reagents such as DAST, selectflour and thereof, or C-alkylation reaction with various alkyl halides in presence of bases such as sodium hydride, potassium tert butoxide , K2CO3, Na 2 C0 3 , CS2CO3 and like; in polar aprotic solvents like DMF, DMSO, acetone and like, etheral solvents such as THF, 1,4-dioxane and like to give compound of formula (R16).
  • Compound of formula (R16) can be converted to compound of formula (I) by analogous protocol mentioned above for the conversion of (R14) to compound of formula (I).
  • the compounds of formula (I) was prepared by following the sequential transformations as depicted and described in Scheme S:
  • Compound of formula (S2) was prepared from compound of formula (SI) by oxidation reaction followed by N-alkylation reaction. This oxidation was effected by reagents like tertiary butyl hydroperoxide, selenium dioxide, manganese dioxide and like; in presence of catalytic Cul, Cu(I) reagents and thereof.
  • N- alkylation was carried out by using alkyl halides in presence of bases such as sodium hydride, potassium /sodium alkoxide bases such as K2CO3, Na2CO3, CS2CO3; organic bases like diisopropylethyl amine, DBU, DABCO and so on; in polar aprotic solvents like DMF, DMSO, acetone and like, etheral solvents such as THF, 1,4-dioxane and like, at room temperature or elevated temperatures provide compound of formula (S2) Compound of formula (S2) undergoes reaction with organometallic reagents such as Grignard reagent, dialkyl zinc , alkyl lithiums, and thereof; silane reagents such as trifluoromethyl trimethyl silane and thereof; in etheral solvents such as THF, MTBE and like to provide compounds of formula (S3)
  • bases such as sodium hydride, potassium /sodium alkoxide bases such as K2CO3, Na2
  • Compound of formula (S3) undergoes O-alkylation to provide compound of formula (S4).
  • This transformation can be effected by using alkyl halides in presence of bases such as sodium hydride, potassium /sodium alkoxide K2CO3, Na2CO3, CS2CO3, sodium hydride; organic bases like diisopropylethyl amine, DBU, DABCO and so on; in polar aprotic solvents like DMF, DMSO, acetone and like, etheral solvents such as THF, 1,4-dioxane and like, at room temperature or elevated temperatures.
  • bases such as sodium hydride, potassium /sodium alkoxide K2CO3, Na2CO3, CS2CO3, sodium hydride
  • organic bases like diisopropylethyl amine, DBU, DABCO and so on
  • polar aprotic solvents like DMF, DMSO, acetone and like, etheral solvents such as THF,
  • Compound of formula (S5) can be prepared from compound of formula (S4) by employing halogenation reaction. Such reactions can be carried out in presence of halogenating reagents such as N-halo succinamide, hydrohaloic acid and likes; in solvents like DMF, Acetic acid and thereof; optionally in presence additives such as trifluoroacetic acid and like, in catalytic or molar proportions; and at room temperature or at elevated temperatures.
  • halogenating reagents such as N-halo succinamide, hydrohaloic acid and likes
  • solvents like DMF such as acetic acid and thereof
  • additives such as trifluoroacetic acid and like, in catalytic or molar proportions
  • compound of formula (S7) can be prepared in three steps.
  • Compound of formula (S4) undergoes nitration reaction to provide compound of formula (S9).
  • This reaction was carried out in presence of nitrating reagents such as potassium nitrate, sodium nitrate nitric acid and like; in acidic solvents such as sulfuric acid and thereof.
  • Compound of formula (S9) undergoes reduction reaction to provide compound of formula (S10).
  • reducing agents include hydrogenation with palladium on carbon, metal reductions like iron, tin or tin chloride and the like.
  • reducing agents include hydrogenation with palladium on carbon, metal reductions like iron, tin or tin chloride and the like.
  • These reactions are carried out in one or more solvents, e.g., ethers such as THF, 1,4-dioxane, and the like; alcohol such as methanol, ethanol and the like; under acidic conditions involving ammonium clhoride, acetic acid, hydrochloric acid and the like mixtures thereof
  • Compound of formula (S7) allowed to react with phosporyl halides such as POCh or POBr3 optionally in solvents such as toluene, xylene, chlorobenzene or the like or the mixtures thereof, optionally using organic base such as triethylamine, diisopropylethylamine or the like to provide compound of formula (S8).
  • Compound of formula (S8) allowed to react with compound of formula (A5) in presence of suitable coupling reagent to provide compound of formula (I).
  • reaction can be carried out in presence of organic base such as diisopropylethylamine, triethylamine, DBU or the like, or using coupling reagents such as DCC, EDC, BOP, pyBOP, HBTU or the like; either neat or in etheral solvents such as THF, 1,4 dioxane and like or polar aprotic solvents like DMF, DMA, DMSO and thereof
  • organic base such as diisopropylethylamine, triethylamine, DBU or the like
  • coupling reagents such as DCC, EDC, BOP, pyBOP, HBTU or the like
  • etheral solvents such as THF, 1,4 dioxane and like or polar aprotic solvents like DMF, DMA, DMSO and thereof
  • compound of formula (S2) undergoes difluorination reaction with reagents such as DAST, selectfluor and like, in chlorinated solvent like dich
  • Compound of formula (Sll) can be converted to compound of formula (I) by employing analogous five step protocol as mentioned above for conversion of compound of formula (S4) to compound of formula (I). Further, Compound of formula (Sll) can be converted to compound of formula (S 14) by employing analogous three step protocol as mentioned above for conversion of compound of formula (S4) to compound of formula (S7) via compound of formula (S5) followed by compound of formula (S6).
  • Compound of formula (S14) can be converted to compound of formula (I) by employing analogous two step protocol as mentioned above for conversion of compound of formula (S7) to compound of formula (I).
  • Compound of formula (I) further on reaction with various organometallic reagents like LiAlH4,BH3-DMS and like provide compound of formula (I) These reactions are carried out in one or more solvents, e.g., ethers such as THF, 1,4-dioxane, and the like
  • Nitration of compound of formula (Tl) with nitrating reagents such as, although not limited to fuming nitric acid, potassium nitrate, and the like in acids such as, although not limited to tin (IV) chloride, sulphuric acid, trifluoracetic acid, acetic acid and the like, anhydrides like acetic anhydride, trifluoracetic anhydride and the like, or mixture(s) thereof to provide compound of formula (T2).
  • Compound of formula (T2) undergoes esterification reaction to corresponding compound of formula (T3) using solvents such as methanol, ethanol, propanol, tot-butanol using acidic conditions like hydrochloric acid, sulfuric acid, thionyl chloride or the like or mixture(s) thereof.
  • solvents such as methanol, ethanol, propanol, tot-butanol using acidic conditions like hydrochloric acid, sulfuric acid, thionyl chloride or the like or mixture(s) thereof.
  • Compound of formula (T3) derivative undergoes N-alkylation reaction to corresponding compound of formula (T4) using alkylamine and solvents such as methanol, ethanol, propanol, tert-butanol.
  • Compound of formula (T6) undergoes N-alkylation using alkyl halides in presence of bases such as sodium hydride, potassium /sodium alkoxide K2CO3, Na2CO3, CS2CO3; organic bases like diisopropylethyl amine, DBU, DABCO and so on; in polar aprotic solvents like DMF, DMSO, acetone and like, etheral solvents such as THF, 1,4-dioxane and like, at room temperature or elevated temperatures provide compound of formula (T7).
  • bases such as sodium hydride, potassium /sodium alkoxide K2CO3, Na2CO3, CS2CO3
  • organic bases like diisopropylethyl amine, DBU, DABCO and so on
  • polar aprotic solvents like DMF, DMSO, acetone and like
  • etheral solvents such as THF, 1,4-dioxane and like
  • Compound of formula (T8) undergoes deprotection using acids like organic acids such as trifluoroacetic acid, Methane sulfonic acid and like, mineral acids like hydrochloric acid, acetic acid (Aqueous or in etheral solvents), sulfuric acid and the like; using solvents like dichloromethane, dichloroethane, THF, 1,4-dioxane and like thoeof to provide compound of formula (T9).
  • acids like organic acids such as trifluoroacetic acid, Methane sulfonic acid and like, mineral acids like hydrochloric acid, acetic acid (Aqueous or in etheral solvents), sulfuric acid and the like.
  • solvents like dichloromethane, dichloroethane, THF, 1,4-dioxane and like thoeof to provide compound of formula (T9).
  • Compound of formula (T10) allowed to react with phosporyl halides such as POCI3 or POBr3 optionally in solvents such as toluene, xylene, chlorobenzene or the like or the mixtures thereof, optionally using organic base such as triethylamine, diisopropylethylamine or the like to provide compound of formula (T11).
  • phosporyl halides such as POCI3 or POBr3
  • solvents such as toluene, xylene, chlorobenzene or the like or the mixtures thereof, optionally using organic base such as triethylamine, diisopropylethylamine or the like
  • organic base such as triethylamine, diisopropylethylamine or the like
  • the reaction can be carried out in presence of organic base such as diisopropylethylamine, triethylamine, DBU or the like, or using coupling reagents such as DCC, EDC, BOP, pyBOP, HBTU or the like; in etheral solvents such as THF, 1,4 dioxane and like or polar aprotic solvents like DMF, DMA, DMSO and thereof.
  • organic base such as diisopropylethylamine, triethylamine, DBU or the like
  • coupling reagents such as DCC, EDC, BOP, pyBOP, HBTU or the like
  • etheral solvents such as THF, 1,4 dioxane and like or polar aprotic solvents like DMF, DMA, DMSO and thereof.
  • the reaction can be carried out in presence of organic base such as diisopropylethylamine, triethylamine, DBU or the like, or using coupling reagents such as DCC, EDC, BOP, pyBOP, HBTU or the like; in etheral solvents such as THF, 1,4 dioxane and like or polar aprotic solvents like DMF, DMA, DMSO and thereof.
  • organic base such as diisopropylethylamine, triethylamine, DBU or the like
  • coupling reagents such as DCC, EDC, BOP, pyBOP, HBTU or the like
  • etheral solvents such as THF, 1,4 dioxane and like or polar aprotic solvents like DMF, DMA, DMSO and thereof.
  • Reduction of compound of the formula (U4) provide compound of formula (US).
  • the reduction of nitre group was carried out using different reagents; although not limited, such reducing agents include hydrogenation with palladium on carbon, metal reductions like iron, tin or tin chloride and the like. These reactions are carried out in one or more solvents, e.g., ethers such as THF, 1,4-dioxane, and the like; alcohol such as methanol, ethanol and the like; under acidic conditions involving ammonium chloride, acetic acid, hydrochloric acid and the like mixtures thereof. Cyclization of compound of the formula (U5) using corresponding ketone in acid catalyst like pTsOH, Benzene sulphonic acid, sulfuric acid and acetic acid at room temperature or elevated temperatures provided compound of formula (U6).
  • Compound of formula (V2) can be prepared from compound of formula (VI) via reductive cyclization reaction. This transformations can be carried out using reducing reagents such as contact hydrogenation in presence of Raney nickel, Pd/C, Pt/C and like; in etheral solvents such as 1,4-dioxane and like; optionally at room temperature or at elevated temperatures.
  • reducing reagents such as contact hydrogenation in presence of Raney nickel, Pd/C, Pt/C and like
  • etheral solvents such as 1,4-dioxane and like
  • Compound of formula (V2) undergoes diazotization reaction using tot-butyl nitrite, isoamyl nitrite, sodium nitrite and like; followed by reaction with copper halides and like; can provide compound of formula (V3)
  • Compound of formula (V3) undergoes C-alkylation and N-alkylation simultaneously in presence of alkyl halides in presence of bases such as sodium hydride, potassium /sodium alkoxide K2CO3, Na2CO3, CS2CO3; organic bases like diisopropylethyl amine, DBU, DABCO and so on; in polar aprotic solvents like DMF, DMSO, acetone and like, etheral solvents such as THF, 1,4-dioxane and like, at room temperature or elevated temperatures provide compound of formula (V4)
  • Compound of formula (V4) can be converted to compound of formula (I) by employing analogous 3 step protocol mentioned in scheme-P for conversion of compound of formula (P6) to compound of formula (I).
  • Compound of formula (Wl) undergoes esterification reaction to provide compound of formula (W2).
  • This transformation can be effected by reaction of alcohols such as methanol, ethanol and like; in presence of mineral acids like sulfuric acid, organic acids like methane sulfonic acid and like, or in presence of chloride reagents like thionyl chloride, oxalyl chloride and thereof.
  • This transformation can also be effected by Mitsonobu reaction between acid (Wl) and corresponding alcohols in presence of Triaryl phosphines and azocarboxylates such as DEAD, DIAD and like.
  • Compound of formula (W2) undergoes benzylic halogenation reaction using halogenating reagents like N-halo succinimide and thereof; in presence of initiators such as benzoyl peroxide, AIBN and like; in solvents such as carbon tetrachloride and thereof; at elevated temperature provide compound of formula (W3).
  • Compound of formula (W4) undergoes C-alkylation and N-alkylation simultaneously in presence of alkyl halides in presence of bases such as sodium hydride, potassium /sodium alkoxide K2CO3, Na2CO3, CS2CO3; organic bases like diisopropylethyl amine, DBU, DABCO and so on; in polar aprotic solvents like DMF, DMSO, acetone and like, etheral solvents such as THF, 1,4-dioxane and like, at room temperature or elevated temperatures provide compound of formula (W5).
  • bases such as sodium hydride, potassium /sodium alkoxide K2CO3, Na2CO3, CS2CO3
  • organic bases like diisopropylethyl amine, DBU, DABCO and so on
  • polar aprotic solvents like DMF, DMSO, acetone and like, etheral solvents such as THF, 1,4-dioxane and like
  • Compound of formula (W6) undergoes hydrolysis reaction to furnish compound of formula (W7).
  • This transformation can be carried out in presence of alkali hydroxides such as NaOH, LiOH and thereof, in solvents like methanol, ethanol and thereof or using solvents like DMF, THF, 1,4-dioxane.
  • Compound of formula (W7) can be converted to compound of formula (I) by employing analogous 3 step protocol mentioned in scheme P for conversion of compound of formula (P6) to compound of formula (I).
  • Compound of formula (Y4) undergoes N-alkylation using alkyl halides in presence of bases such as NaH, Potassium/sodium alkoxides, K2CO3, Na2CO3, CS2CO3; organic bases like diisopropylethyl amine, DBU, DABCO and so on; in polar aprotic solvents like DMF, DMSO, acetone and like, etheral solvents such as THF, 1,4-dioxane and like, at room temperature or elevated temperatures provide compound of formula (Y5).
  • bases such as NaH, Potassium/sodium alkoxides, K2CO3, Na2CO3, CS2CO3
  • organic bases like diisopropylethyl amine, DBU, DABCO and so on
  • polar aprotic solvents like DMF, DMSO, acetone and like
  • etheral solvents such as THF, 1,4-dioxane and like
  • Compound of formula (Y6) undergoes deprotection in acidic conditions using organic acids such as trifluoroacetic acid, Methane sulfonic acid and like, mineral acids like hydrochloric acid, acetic acid (aqueous or in etheral solvents), sulfuric acid and the like; using solvents like dichloromethane, dichloroethane, THF, 1,4-dioxane and like thereof to provide compound of formula (Y7).
  • Compound of formula (Y7) allowed to react with alkylnitrile in presence of the acidic reagents such as methane sulfonic acid, sulfuric acid, hydrochloric acid or the like to obtain compound of formula (Y8).
  • the same transformation can be carried out using trialkyl orthoacetate in presence of ammonium acetate, in corresponding polar protic solvents like ethanol, methanol and thereof.
  • Compound of formula (Y9) allowed to react with compound of formula (A5) in presence of suitable coupling reagent to provide compound of formula (I).
  • the reaction can be carried out in presence of organic base such as diisopropylethylamine, triethylamine, DBU or the like, or using coupling reagents such as DCC, EDC, BOP, pyBOP, HBTU or the like; in etheral solvents such as THF, 1,4 dioxane and like or polar aprotic solvents like DMF, DMA, DMSO and like, at elevated temperatures.
  • organic base such as diisopropylethylamine, triethylamine, DBU or the like
  • coupling reagents such as DCC, EDC, BOP, pyBOP, HBTU or the like
  • etheral solvents such as THF, 1,4 dioxane and like or polar aprotic solvents like DMF, DMA, DMSO and like
  • Compound of formula (Zl) undergoes oxidation reaction using oxidizing reagents such as tertiary butyl hydroperoxide, selenium dioxide, manganese dioxide and like; in presence of catalytic Cul , Cu(I) reagents and thereof; to provide compound of formula (Z2).
  • oxidizing reagents such as tertiary butyl hydroperoxide, selenium dioxide, manganese dioxide and like
  • catalytic Cul Cu(I) reagents and thereof
  • Compound of formula (Z3) can be obtained from compound of formula (Z2) by employing carbonyl protection reaction using diols such as 2,2-dimethylpropane-l,3-diol and like; in presence of mild acidic reagents such as PTSA and thereof; using hydrocarbon solvents like cyclohexane and like.
  • Compound of formula (Z5) can be converted to compound of formula (Z8) by employing analogous 3 step protocol mentioned in scheme P for conversion of compound of formula (P6) to compound of formula (I).
  • Compound of formula (Z8) on ketal deprotection in acidic medium provide compound of formula (I). This transformation was done by employing mineral acids such as HC1, H2SO4 and like; by employing solvents such as 1,4-dioxane, THF, acetic acid and like.
  • Compound of formula (I) can be converted to compound of formula (I) by Wolff kishner reduction using hydroxyl amine hydrochloride reduction in alkaline medium. Such transformation can also be carried out by using Clemmensen reduction reaction in acidic medium.
  • the compounds of formula (I) was prepared by following the sequential transformations as depicted and described in Scheme-AA herein below Compound of formula (AA1) on henry’s reaction with nitroalkane in basic medium provided compound of formula (AA2). Such transformations can be carried out in presence of organic bases such as DIPEA, DABCO, and DBU and like, using nitroalkanes as solvent.
  • organic bases such as DIPEA, DABCO, and DBU and like
  • Compound of formula (AA2) on nitro reduction provided compound of formula (AA3).
  • the reduction of nitro group was carried out using different reagents; although not limited, such reducing agents include hydrogenation with palladium on carbon, metal reductions like iron, tin or tin chloride and the like. These reactions are carried out in one or more solvents, e.g., ethers such as THF, 1,4-dioxane, and the like; alcohol such as methanol, ethanol and the like; under acidic conditions involving ammonium chloride, acetic acid, hydrochloric acid and mixtures thereof.
  • solvents e.g., ethers such as THF, 1,4-dioxane, and the like
  • alcohol such as methanol, ethanol and the like
  • acidic conditions involving ammonium chloride, acetic acid, hydrochloric acid and mixtures thereof.
  • Compound of formula (AA3) undergoes carbamate formation reaction mediated by reagents such as using CDI in polar aprotic solvents like DMF, DMSO, halogenated solvents like DCM, chloroform, ethereal solvents like THF, 1,4-dioxane, at room temperature or elevated temperatures provided compound of formula (AA4)
  • Compound of formula (AA4) undergoes N-alkylation using alkyl halides and bases such as K2CO3, Na2CO3, CS2CO3; organic bases like diisopropylethyl amine, DBU, DAB CO and so on; in polar aprotic solvents like DMF, DMSO, acetone and like, etheral solvents such as THF, 1,4-dioxane and like, at room temperature or elevated temperatures provide compound of formula (AA5)
  • Compound of formula (AB1) undergoes Aldol type reaction with aldehydes and ketones viz. acetaldehyde in presence of secondary amines such as diethyl amine, pyrrolidine and like, provide aldol intermediate which further on carbonyl reduction using NaBH 4 and like, in alcohol solvents such as methanol, ethanol and mixtures thereof provide diol compound of formula (AB2)
  • Compound of formula (AB2) undergoes O-alkylation reaction with alkyl halides in presence of bases such as NaH, sodium/potassium alkoxides, K2CO3, Na2CO3, CS2CO3; organic bases like diisopropylethyl amine, DBU, DABCO and so on; in polar aprotic solvents like DMF, DMSO, acetone and like, etheral solvents such as THF, 1, 4-dioxane and like, at room temperature or elevated temperatures provide compound of formula (AB3)
  • Compound of formula (AB3) undergoes nitration reaction to provide compound of formula (AB4). This reaction was carried out in presence of nitrating reagents such as potassium nitrate, sodium nitrate nitric acid and like; in acidic solvents such as sulfuric acid and thereof.
  • Compound of formula (AB4) undergoes reduction reaction to provide compound of formula (AB5).
  • reducing agents include hydrogenation with palladium on carbon, metal reductions like iron, tin or tin chloride and the like.
  • These reactions are carried out in one or more solvents, e.g., ethers such as THF, 1,4-dioxane, and the like; alcohol such as methanol, ethanol and the like; under acidic conditions involving ammonium chloride, acetic acid, hydrochloric acid and the like mixtures thereof
  • Compound of formula (AB5) allowed to react with alkyl nitrile in presence of the acidic reagents such as methanesulfonic acid, sulfuric acid, hydrochloric acid, or the like to obtain compound of formula (AB6).
  • the same transformation can be carried out using trialkyl orthoacetate in presence of ammonium acetate, in corresponding polar protic solvents like ethanol, methanol and thereof.
  • Compound of formula (AB7) allowed to react with compound of formula (A5) in presence of suitable coupling reagent to provide compound of formula (I).
  • the reaction can be carried out in presence of organic base such as diisopropylethylamine, triethylamine, DBU or the like, or using coupling reagents such as DCC, EDC, BOP, pyBOP, HBTU or the like; in etheral solvents such as THF, 1,4 dioxane and like or polar aprotic solvents like DMF, DMA, DMSO and thereof
  • Compound of formula (Q9) undergoes coupling reaction with compound of formula (AS) to furnish compound of formula (I).
  • the reaction can be carried out in presence of organic base such as diisopropylethylamine, triethylamine, DBU or the like, or using coupling reagents such as DCC, EDC, BOP, pyBOP, HBTU or the like; either neat reaction in base or in etheral solvents such as THF, 1 ,4 dioxane and like or polar aprotic solvents like DMF, DMA, DMSO and thereof
  • the compound of formula (AC1) was subjected to C-C coupling reaction e.g. suzuki coupling reaction with corresponding boronic acid or boronic ester to provide compound of formual (AC2).
  • This reaction can mediated by a suitable catalyst such as, e.g., Pd(PPh 3 ) 2 Cl 2 , Pd2dba3, Pd(PPli3)4, PdCl2(dppf).DCM adduct or mixtures thereof; in the presence of suitable base, preferably inorganic bases such as K2CO3, Na2CO3, CS2CO3, NaO t Bu, Potassium phosphate, or mixture thereof.
  • Such reactions can be carried out in solvents like, e.g., ethers such as THF, 1,4-Dioxane and the like; hydrocarbons, e.g., toluene; amides such as DMF, DMA or mixtures thereof
  • Compound of formula (AC2) undergoes hydrogenation reaction in presence of catalyst such as Pd(OH)2 on carbon, palladium on carbon, and the like; in one or more solvents e.g alcohol such as methanol, ethanol and the like; under acidic conditions involving ammonium chloride, acetic acid, hydrochloric acid and mixtures thereof, optionally in presence of water to provide compound of formula (AC3)
  • catalyst such as Pd(OH)2 on carbon, palladium on carbon, and the like
  • solvents e.g alcohol such as methanol, ethanol and the like
  • Compound of formula (AC3) undergoes deprotection reaction mediated by acids such as organic acids e,g trifluoroacetic acid, Methane sulfonic acid and the like, mineral acids e.g hydrochloric acid, acetic acid (Aqueous or in etheral solvents), sulfuric acid and the like; using solvents like dichloromethane, dichloroethane, THF, 1,4-dioxane and mixtures thereof to provide compound of formula (I)
  • acids such as organic acids e,g trifluoroacetic acid, Methane sulfonic acid and the like, mineral acids e.g hydrochloric acid, acetic acid (Aqueous or in etheral solvents), sulfuric acid and the like; using solvents like dichloromethane, dichloroethane, THF, 1,4-dioxane and mixtures thereof to provide compound of formula (I)
  • the intermediates and the compounds of the present invention can be obtained in a pure form by any suitable method, for example, by distilling off the solvent in vacuum and/or re -crystallizing the residue obtained from a suitable solvent, such as pentane, diethyl ether, isopropyl ether, chloroform, dichloromethane, ethyl acetate, acetone or their combinations or subjecting it to one of the purification methods, such as column chromatography (e.g., flash chromatography) on a suitable support material such as alumina or silica gel using an eluent such as dichloromethane, ethyl acetate, hexane, methanol, acetone and/or their combinations.
  • a suitable solvent such as pentane, diethyl ether, isopropyl ether, chloroform, dichloromethane, ethyl acetate, acetone or their combinations
  • the purification methods such as column chromatography
  • work-up includes distribution of the reaction mixture between the organic and aqueous phase indicated within parentheses, separation of the layers and drying of the organic layer over sodium sulphate, filtration, and evaporation of the solvent.
  • Purification includes purification by silica gel chromatographic techniques, generally by using a mobile phase with suitable polarity, and purification using selective crystallization.
  • Salts of compound of formula (I) can be obtained by dissolving the compound in a suitable solvent, for example in a chlorinated hydrocarbon, such as methyl chloride or chloroform or a low molecular weight aliphatic alcohol, for example, ethanol or isopropanol, which is then treated with the desired acid or base as described in Berge S. M. et al., “Pharmaceutical Salts, a review article in Journal of Pharmaceutical sciences volume 66, page 1-19 (1977)” and in “Handbook of Pharmaceutical Salts - Properties, Selection, and Use ” by P. Heinrich Stahland Camille G. Wermuth, Wiley- VCH (2002).
  • a suitable solvent for example in a chlorinated hydrocarbon, such as methyl chloride or chloroform or a low molecular weight aliphatic alcohol, for example, ethanol or isopropanol
  • the salt can be of an alkali metal (e.g., sodium or potassium), alkaline earth metal (e.g., calcium), or ammonium.
  • the compound of the invention or a composition thereof can potentially be administered as a pharmaceutically acceptable acid-addition, base neutralized or addition salt, formed by reaction with an inorganic acid, such as hydrochloric acid, hydrobromic acid, perchloric acid, nitric acid, thiocyanic acid, sulfuric acid, and phosphoric acid, and organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, and fumaric acid, or by reaction with an inorganic base, such as sodium hydroxide or potassium hydroxide.
  • an inorganic acid such as hydrochloric acid, hydrobromic acid, perchloric acid, nitric acid, thiocyanic acid, sulfuric acid, and phosphoric acid
  • organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid
  • the conversion to a salt is accomplished by treatment of the base compound with at least a stoichiometric amount of an appropriate acid.
  • the free base is dissolved in an inert organic solvent such as diethyl ether, ethyl acetate, chloroform, ethanol, methanol, and the like, and the acid is added in a similar solvent.
  • the mixture is maintained at a suitable temperature (e.g., between 0UC and 50UC).
  • the resulting salt precipitates spontaneously or can be brought out of solution with a less polar solvent.
  • stereoisomers of the compounds of formula (I) of the present invention can be prepared by stereospecific synthesis or resolution of racemic compound mixture by using an optically active amine, acid or complex forming agent, and separating the diastereomeric salt/complex by fractional crystallization or by column chromatography.
  • Prodrugs of the compounds of the invention can be prepared in situ during the isolation and purification of the compounds, or by separately reacting the purified compound with a suitable derivatizing agent. For example, hydroxy groups can be converted to ester groups via treatment with a carboxylic acid in the presence of a catalyst.
  • cleavable alcohol prodrug moieties include substituted or unsubstituted, branched or unbranched lower alkyl ester moieties, e.g., ethyl esters, lower alkenyl esters, di-lower alkylamino lower-alkyl esters, e.g., dimethyl aminoethyl ester, acylamino lower alkyl esters, acyloxy lower alkyl esters (e.g., pivaloyloxymethyl ester), aryl esters, e.g., phenyl ester, aryl -lower alkyl esters, e.g., benzyl ester, optionally substituted, e.g., with methyl, halo, or methoxy substituents aryl and aryl-lower alkyl esters, amides, lower - alkyl amides, di-lower alkyl amides, and hydroxy amides.
  • the compounds of formula (I) of the present invention can exist in tautomeric forms, such as keto-enol tautomer. Such tautomeric forms are contemplated as an aspect of the present invention and such tautomer’s may be in equilibrium or predominant in one of the forms.
  • the present invention also embraces isotopically-labelled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in abundance in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 0, 17 0, 31 P, 32 P, 35 S, 18 F, 36 Cl, and 123 I respectively.
  • the present invention further provides a pharmaceutical composition, containing the compounds of the general formula (I) as defined above, its tautomeric form, its stereoisomer, its polymorph, its solvate, its pharmaceutically acceptable salts in combination with pharmaceutically acceptable carriers, diluents, excipients, and the like.
  • the pharmaceutically acceptable carrier or excipient is preferably one that is chemically inert to the compound of the invention and one that has no detrimental side effects or toxicity under the conditions of use.
  • Such pharmaceutically acceptable carriers or excipients include saline (e.g., 0.9% saline), Cremophor EL ® (which is a derivative of castor oil and ethylene oxide available from Sigma Chemical Co., St.
  • a preferred pharmaceutical carrier is polyethylene glycol, such as PEG 400, and particularly a composition comprising 40% PEG 400 and 60% water or saline. The choice of carrier will be determined in part by the particular compound chosen, as well as by the particular method used to administer the composition. Accordingly, there is a wide variety of suitable formulations of the pharmaceutical composition of the present invention.
  • Formulations for oral, aerosol, parenteral, subcutaneous, intravenous, intraarterial, intramuscular, intrathecal, intraperitoneal, rectal, and vaginal administration can be developed for the compound of formula (I), its tautomeric form, its stereoisomer, its polymorph, its solvate, and its pharmaceutically acceptable salt.
  • compositions for parenteral administration that comprise a solution of the compound of the invention dissolved or suspended in an acceptable carrier suitable for parenteral administration, including aqueous and non-aqueous, isotonic sterile injection solutions.
  • compositions include solutions containing anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives.
  • the compound can be administered in a physiologically acceptable diluent in a pharmaceutical carrier, such as a sterile liquid or mixture of liquids, including water, saline, aqueous dextrose and related sugar solutions, an alcohol, such as ethanol, isopropanol (for example in topical applications), or hexadecyl alcohol, glycols, such as propylene glycol or polyethylene glycol, dimethylsulfoxide, glycerol ketals, such as 2,2-dimethyl-l,3-dioxolane-4-methanol, ethers, such as poly(ethyleneglycol) 400, an oil, a fatty acid, a fatty acid ester or glyceride, or an acetylated fatty acid glyceride, with or without the addition of a pharmaceutically acceptable surfactant, such as a soap or a detergent, suspending agent, such as pectin, carbomers, methylcellulose, hydroxypropylmethylcellulose, or
  • Oils useful in parenteral formulations include petroleum, animal, vegetable, and synthetic oils. Specific examples of oils useful in such formulations include peanut, soybean, sesame, cottonseed, com, olive, petrolatum, and mineral oil. Suitable fatty acids for use in parenteral formulations include oleic acid, stearic acid, and isostearic acid. Ethyl oleate and isopropyl myristate are examples of suitable fatty acid esters.
  • Suitable soaps for use in parenteral formulations include fatty alkali metal, ammonium, and triethanolamine salts
  • suitable detergents include (a) cationic detergents such as, for example, dimethyl dialkyl ammonium halides, and alkyl pyridinium halides, (b) anionic detergents such as, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates, (c) nonionic detergents such as, for example, fatty amine oxides, fatty acid alkanolamides, and polyoxyethylene polypropylene copolymers, (d) amphoteric detergents such as, for example, alkyl ⁇ -aminopropionates, and 2-alkyl-imidazoline quaternary ammonium salts, and (e) mixtures thereof.
  • the parenteral formulations typically will contain from about 0.5% or less to about 25% or more by weight of a compound of the invention in solution. Preservatives and buffers can be used. In order to minimize or eliminate irritation at the site of injection, such compositions can contain one or more nonionic surfactants having a hydrophile-lipophile balance (HLB) of from about 12 to about 17. The quantity of surfactant in such formulations will typically range from about 5% to about 15% by weight. Suitable surfactants include polyethylene sorbitan fatty acid esters, such as sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.
  • HLB hydrophile-lipophile balance
  • parenteral formulations can be presented in unit-dose or multi-dose sealed containers, such as ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid excipient, for example, water, for injections, immediately prior to use.
  • sterile liquid excipient for example, water
  • Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets.
  • Topical formulations including those that are useful for transdermal drug release, are well known to those of skill in the art and are suitable in the context of the present invention for application to skin.
  • Formulations suitable for oral administration can consist of (a) liquid solutions, such as an effective amount of a compound of the invention dissolved in diluents, such as water, saline, or orange juice; (b) capsules, sachets, tablets, lozenges, and troches, each containing a pre -determined amount of the compound of the invention, as sohds or granules; (c) powders; (d) suspensions in an appropriate liquid; and (e) suitable emulsions.
  • liquid solutions such as an effective amount of a compound of the invention dissolved in diluents, such as water, saline, or orange juice
  • diluents such as water, saline, or orange juice
  • capsules, sachets, tablets, lozenges, and troches each containing a pre -determined amount of the compound of the invention, as sohds or granules
  • powders such as sohds or granules
  • Liquid formulations can include diluents, such as water and alcohols, for example, ethanol, benzyl alcohol, and the polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent.
  • diluents such as water and alcohols, for example, ethanol, benzyl alcohol, and the polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent.
  • Capsule forms can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers, such as lactose, sucrose, calcium phosphate, and cornstarch.
  • Tablet forms can include one or more of lactose, sucrose, mannitol, com starch, potato starch, alginic acid, microcrystalline cellulose, acacia, gelatin, guar gum, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid, and other excipients, colorants, diluents, buffering agents, disintegrating agents, moistening agents, preservatives, flavoring agents, and pharmacologically compatible excipients.
  • Lozenge forms can comprise the compound ingredient in a flavor, usually sucrose and acacia or tragacanth, as well as pastilles comprising a compound of the invention in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, and the like containing, in addition to the compound of the invention, such excipients as are known in the art.
  • a flavor usually sucrose and acacia or tragacanth
  • pastilles comprising a compound of the invention in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, and the like containing, in addition to the compound of the invention, such excipients as are known in the art.
  • a compound of the present invention can be made into aerosol formulations to be administered via inhalation.
  • a compound of the invention is preferably supplied in finely divided form along with a surfactant and propellant. Typical percentages of the compounds of the invention can be about 0.01% to about 20% by weight, preferably about 1% to about 10% by weight.
  • the surfactant must, of course, be nontoxic, and preferably soluble in the propellant.
  • Such surfactants are the esters or partial esters of fatty acids containing from 6 to 22 carbon atoms, such as caproic, octanoic, lauric, palmitic, stearic, linoleic, linolenic, olesteric and oleic acids with an aliphatic polyhydric alcohol or its cyclic anhydride.
  • Mixed esters such as mixed or natural glycerides can be employed.
  • the surfactant can constitute from about 0.1% to about 20% by weight of the composition, preferably from about 0.25% to about 5%.
  • the balance of the composition is ordinarily propellant.
  • a carrier can also be included as desired, e.g., lecithin, for intranasal delivery.
  • aerosol formulations can be placed into acceptable pressurized propellants, such as dichlorodifluoromethane, propane, nitrogen, and the like. They also can be formulated as pharmaceuticals for non-pressured preparations, such as in a nebulizer or an atomizer. Such spray formulations can be used to spray mucosa. Additionally, the compound of the invention can be made into suppositories by mixing with a variety of bases, such as emulsifying bases or water-soluble bases. Formulations suitable for vaginal administration can be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulas containing, in addition to the compound ingredient, such carriers as are known in the art to be appropriate.
  • the concentration of the compound in the pharmaceutical formulations can vary, e.g., from less than about 1% to about 10%, to as much as about 20% to about 50% or more by weight, and can be selected primarily by fluid volumes, and viscosities, in accordance with the particular mode of administration selected.
  • a typical pharmaceutical composition for intravenous infusion could be made up to contain 250 ml of sterile Ringer’s solution, and 100 mg of at least one compound of the invention.
  • Actual methods for preparing parenterally administrable compounds of the invention will be known or apparent to those skilled in the art and are described in more detail in, for example, Remington ’s Pharmaceutical Science (17* ed., Mack Publishing Company, Easton, PA, 1985).
  • the compound of the invention can be formulated as inclusion complexes, such as cyclodextrin inclusion complexes, or liposomes.
  • Liposomes can serve to target a compound of the invention to a particular tissue, such as lymphoid tissue or cancerous hepatic cells. Liposomes can also be used to increase the half-life of a compound of the invention. Many methods are available for preparing liposomes, as described in, for example, Szoka et al., Ann. Rev. Biophys. Bioeng., 9, 467 (1980) and U.S. Patents no.4235871, 4501728, 4837028, and 5019369.
  • the compounds of the invention can be administered in a dose sufficient to treat the disease, condition or disorder.
  • doses are known in the art (see, for example, the Physicians ’ Desk Reference (2004)).
  • the compounds can be administered using techniques such as those described in, for example, Wasserman et al., Cancer, 36, pp. 1258-1268 (1975) and Physicians ’ Desk Reference, 58th ed., Thomson PDR (2004).
  • Suitable doses and dosage regimens can be determined by conventional range-finding techniques known to those of ordinary skill in the art. Generally, treatment is initiated with smaller dosages that are less than the optimum dose of the compound of the present invention. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached.
  • the present method can involve the administration of about 0.1 pg to about 50 mg of at least one compound of the invention per kg body weight of the individual. For a 70 kg patient, dosages of from about 10 pg to about 200 mg of the compound of the invention would be more commonly used, depending on a patient’s physiological response.
  • the dose of the pharmaceutically active agent(s) described herein for methods of treating a disease or condition as described above can be about 0.001 to about 1 mg/kg body weight of the subject per day, for example, about 0.001 mg, 0.002 mg, 0.005 mg, 0.010 mg, 0.015 mg, 0.020 mg, 0.025 mg, 0.050 mg, 0.075 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, 0.5 mg, 0.75 mg, or 1 mg/kg body weight per day.
  • the dose of the pharmaceutically active agent(s) described herein for the described methods can be about 1 to about 1000 mg/kg body weight of the subject being treated per day, for example, about 1 mg, 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, 500 mg, 750 mg, or 1000 mg/kg body weight per day.
  • treat do not necessarily imply 100% or complete treatment, amelioration, or inhibition. Rather, there are varying degrees of treatment, amelioration, and inhibition of which one of ordinary skill in the art recognizes as having a potential benefit or therapeutic effect.
  • the disclosed methods can provide any amount of any level of treatment, amelioration, or inhibition of the disorder in a mammal.
  • a disorder, including symptoms or conditions thereof may be reduced by, for example, 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 10%.
  • the treatment, amelioration, or inhibition provided by the inventive method can include treatment, amelioration, or inhibition of one or more conditions or symptoms of the disorder, e.g., cancer.
  • treatment,” “amelioration,” or “inhibition” can encompass delaying the onset of the disorder, or a symptom or condition thereof.
  • the term subject includes an “animal” which in turn includes a mammal such as, without limitation, the order Rodentia, such as mice, and the order Lagomorpha, such as rabbits.
  • the mammals are from the order Carnivora, including Felines (cats) and Canines (dogs).
  • the mammals are from the order Artiodactyla, including Bovines (cows) and Swine (pigs) or of the order Perssodactyla, including Equines (horses).
  • the mammals are of the order Primates, Ceboids, or Simoids (monkeys) or of the order Anthropoids (humans and apes).
  • the mammal is human.
  • the present invention provides a pharmaceutical composition, containing the compound of the general formula (I) as defined herein, its tautomeric form, and its stereoisomer, its polymorph, its solvate, or its pharmaceutically acceptable salt in combination with the usual pharmaceutically employed carriers, diluents, and the like are useful for the treatment of a disease or disorder mediated through SOS1.
  • the present invention provides a pharmaceutical composition, containing the compound of the general formula (I) as defined herein, its tautomeric form, its stereoisomer, its polymorph, its solvate, or its pharmaceutically acceptable salt in combination with the usual pharmaceutically employed carriers, diluents, and the like are useful for the treatment of a disease or disorder such as cancer, infectious disease or disorder, or RASopathy disease or disorder.
  • a disease or disorder such as cancer, infectious disease or disorder, or RASopathy disease or disorder.
  • the present invention provides the compound of formula I, its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, its solvate, its combination with suitable medicament, or its pharmaceutical composition for treating disease characterized by excessive or abnormal cell proliferation such as cancer.
  • the present invention provides the compound of formula I, its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, its solvate, its combination with suitable medicament, or its pharmaceutical composition for treating diseases like pancreatic cancer, lung cancer, colorectal cancer, class 3 BRAF-mutant cancers, hematological cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukaemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B cell lymphoma, esophageal cancer, chronic lymphocytic leukaemia, hepatocellular cancer, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer, Pure mucosal neuroma syndrome, Fibrous Epulis, and sarcomas.
  • diseases like pancreatic cancer, lung cancer, colorectal
  • Compounds belonging to this invention can be used for the treatment of the various cancers mentioned below which harbor hyperactive or aberrantly activated signaling pathways involving SOS1 proteins.
  • Compounds belonging to this invention can be used for the treatment of the various cancers mentioned below which harbor hyperactive or aberrantly activated signaling pathways involving RAS and or SOS1 proteins.
  • the compounds, its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, or its solvate its combination with suitable medicament, its pharmaceutical composition thereof as described hereinbelow can be suitable for treating diseases characterized by excessive or abnormal cell proliferation such as cancer.
  • the cancer, tumor, and other proliferative diseases can be treated with the compounds of the present invention is but not limited to:
  • Cancers of the head and neck e.g. cancers of nasal cavity, paranasal sinuses, nasopharynx, oral cavity (including lip, gum, alveolar ridge, retromolar trigone, floor of mouth, tongue, hard palate, buccal mucosa), oropharynx (including base of tongue, tonsil, tonsillar pillar, soft palate, tonsillar fossa, pharyngeal wall), middle ear, larynx (including supraglottis, glottis, subglottis, vocal cords, hypopharynx, salivary glands (including minor salivary glands).
  • oral cavity including lip, gum, alveolar ridge, retromolar trigone, floor of mouth, tongue, hard palate, buccal mucosa
  • oropharynx including base of tongue, tonsil, tonsillar pillar, soft palate, tonsillar fossa, pharyngeal wall
  • middle ear larynx (including supraglottis,
  • NSCLC non-small cell lung cancer
  • SCLC small cell lung cancer
  • neurogenic tumors including neurofibroma, neurilemoma, malignant schwannoma, neurosarcoma, ganglioneuroblastoma, ganglioneuroma, neuroblastoma, pheochromocytoma, paraganglioma), germ cell tumors (including seminoma, teratoma, nonseminoma), thymic tumors (including thymoma, thymolipoma, thymic carcinoma, thymic carcinoid), mesenchymal tumors (including fibroma, fibrosarcoma, lipoma, liposarcoma, myxoma, mesothelioma, leiomyoma, leiomyosarcoma, rhabdomyosarcoma, xanthogranuloma, mesenchymoma, hemangioma, hemangioendothelioma, hemangioperi
  • GI gastrointestinal
  • cancers of the gastrointestinal (GI) tract e.g. cancers of the esophagus, stomach (gastric cancer), esophagiogastric adenocarcinoma pancreas, liver and biliary tree (including hepatocellular carcinoma (HCC), e.g. childhood HCC, fibrolamellar HCC, combined HCC, spindle cell HCC, clear cell HCC, giant cell HCC, carcinosarcoma HCC, sclerosing HCC; hepatoblastoma; cholangiocarcinoma.
  • HCC hepatocellular carcinoma
  • Cholangiocellular carcinoma hepatic cystadenocarcinoma; angiosarcoma, hemangioendothelioma, leiomyosarcoma, malignant schwannoma, fibrosarcoma, Klatskin tumor), gall bladder, extrahepatic bile ducts, small intestine (including duodenum, jejunum, ileum), large intestine (including cecum, colon, rectum, anus; colorectal cancer, gastrointestinal stroma tumor (GIST)), genitourinary system (including kidney, e.g.
  • renal pelvis renal cell carcinoma (RCC), nephroblastoma (Wilms' tumor), hypernephroma, Grawitz tumor, ureter; urinary bladder, e.g. urachal cancer, urothelial cancer; urethra, e.g. distal, bulbomembranous, prostatic; prostate (androgen dependent, androgen independent, castration resistant, hormone independent, hormone refractory), penis).
  • RCC renal cell carcinoma
  • nephroblastoma Wang tumor
  • hypernephroma Grawitz tumor
  • ureter ureter
  • urinary bladder e.g. urachal cancer, urothelial cancer
  • urethra e.g. distal, bulbomembranous, prostatic
  • prostate androgen dependent, androgen independent, castration resistant, hormone independent, hormone refractory
  • Gynecologic cancers e.g. cancers of the ovary, fallopian tube, peritoneum, cervix, vulva, vagina, uterine body (including endometrium, fundus).
  • carcinoma infiltrating ductal, colloid, lobular invasive, tubular, adenocystic, papillary, medullary, mucinous
  • hormone receptor positive breast cancer estrogen receptor positive breast cancer, progesterone receptor positive breast cancer
  • Her2 positive breast cancer triple negative breast cancer
  • Paget's disease of the breast e.g. mammary carcinoma (infiltrating ductal, colloid, lobular invasive, tubular, adenocystic, papillary, medullary, mucinous), hormone receptor positive breast cancer (estrogen receptor positive breast cancer, progesterone receptor positive breast cancer), Her2 positive breast cancer, triple negative breast cancer, Paget's disease of the breast.
  • cancers of the endocrine system e.g. cancers of the endocrine glands, thyroid gland (thyroid carcinomas/tumors; papillary, follicular, anaplastic, medullary), parathyroid gland (parathyroid carcinoma/tumor), adrenal cortex (adrenal cortical carcinoma/tumors), pituitary gland (including prolactinoma, craniopharyngioma), thymus, adrenal glands, pineal gland, carotid body, islet cell tumors, paraganglion, pancreatic endocrine tumors (PET; non-functional PET, PPoma, gastrinoma, insulinoma, VIPoma, glucagonoma, somatostatinoma, GRFoma, ACTHoma), carcinoid tumors.
  • thyroid gland thyroid carcinomas/tumors
  • parathyroid gland parathyroid carcinoma/t
  • Sarcomas of the soft tissues e.g. fibrosarcoma, fibrous histiocytoma, liposarcoma, leiomyosarcoma, rhabdomyosarcoma, angiosarcoma, lymphangiosarcoma, Kaposi's sarcoma, glomus tumor, hemangiopericytoma, synovial sarcoma, giant cell tumor of tendon sheath, solitary fibrous tumor of pleura and peritoneum, diffuse mesothelioma, malignant peripheral nerve sheath tumor (MPNST), granular cell tumor, clear cell sarcoma, melanocytic schwannoma, plexosarcoma, neuroblastoma, ganglioneuroblastoma, neuroepithelioma, extraskeletal Ewing's sarcoma, paraganglioma, extraskeletal chondrosarcoma, extraskeletal osteosarcoma, mesenchy
  • Sarcomas of the bone e.g. myeloma, reticulum cell sarcoma, chondrosarcoma (including central, peripheral, clear cell, mesenchymal chondrosarcoma), osteosarcoma (including parosteal, periosteal, high-grade surface, small cell, radiation-induced osteosarcoma, Paget's sarcoma), Ewing's tumor, malignant giant cell tumor, adamantinoma, (fibrous) histiocytoma, fibrosarcoma, chordoma, small round cell sarcoma, hemangioendothelioma, hemangiopericytoma, osteochondroma, osteoid osteoma, osteoblastoma, eosinophilic granuloma, chondroblastoma;
  • Mesothelioma e.g. pleural mesothelioma, peritoneal mesothelioma.
  • Cancers of the skin e.g. basal cell carcinoma, squamous cell carcinoma, Merkel's cell carcinoma, melanoma (including cutaneous, superficial spreading, lentigo maligna, acral lentiginous, nodular, intraocular melanoma), actinic keratosis, eyelid cancer, class 3 BRAF-mutant melanoma.
  • Neoplasms of the central nervous system and brain e.g. astrocytoma (cerebral, cerebellar, diffuse, fibrillary, anaplastic, pilocytic, protoplasmic, gemistocytary), glioblastoma, gliomas, oligodendrogliomas, oligoastrocytomas, ependymomas, ependymoblastomas, choroid plexus tumors, medulloblastomas, meningiomas, schwannomas, hemangioblastomas, hemangiomas, hemangiopericytomas, neuromas, ganglioneuromas, neuroblastomas, retinoblastomas, neurinomas (e.g. acoustic), spinal axis tumors.
  • astrocytoma Cerebral, cerebellar, diffuse, fibrillary, anaplastic, pilocytic, protoplasmic, gemistocytary
  • B-cell non-Hodgkin lymphomas including small lymphocytic lymphoma (SLL), lymphoplasmacytoid lymphoma (LPL), mantle cell lymphoma (MCL), follicular lymphoma (FL), diffuse large cell lymphoma (DLCL), Burkitt's lymphoma (BL)), T-cell non- Hodgkin lymphomas (including anaplastic large cell lymphoma (ALCL), adult T-cell leukemia/lymphoma (ATLL), cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma (PTCL)), lymphoblastic T-cell lymphoma (T-LBL), adult T-cell lymphoma, lymphoblastic B-cell lymphoma (B-LBL), immunocytoma, chronic B-cell lymphocytic leukemia (B-CLL), chronic T-cell lymphocytic leukemia (B-CLL), chronic T-cell lymphocytic leukemia
  • Epithelial cancers e.g. squamous cell carcinoma (SCC) (carcinoma in situ, superficially invasive, verrucous carcinoma, pseudosarcoma, anaplastic, transitional cell, lymphoepithelial), adenocarcinoma (AC) (well-differentiated, mucinous, papillary, pleomorphic giant cell, ductal, small cell, signet-ring cell, spindle cell, clear cell, oat cell, colloid, adenosquamous, mucoepidermoid, adenoid cystic), mucinous cystadenocarcinoma, acinar cell carcinoma, large cell carcinoma, small cell carcinoma, neuroendocrine tumors (small cell carcinoma, paraganglioma, carcinoid), oncocytic carcinoma, and
  • Nonepithelial cancers e.g. sarcomas (fibrosarcoma, chondrosarcoma, rhabdomyosarcoma, leiomyosarcoma, hemangiosarcoma, giant cell sarcoma, lymphosarcoma, fibrous histiocytoma, liposarcoma, angiosarcoma, lymphangiosarcoma, neurofibrosarcoma), lymphoma, melanoma, germ cell tumors, hematological neoplasms, mixed and undifferentiated carcinomas.
  • sarcomas fibrosarcoma, chondrosarcoma, rhabdomyosarcoma, leiomyosarcoma, hemangiosarcoma, giant cell sarcoma, lymphosarcoma, fibrous histiocytoma, liposarcoma, angiosarcoma, lymphangiosarcoma, neurofibrosar
  • All cancers mentioned above which are characterized by their specific location or origin in the body are meant to include both the primary tumors and the metastatic tumors derived therefrom. All cancers mentioned above may be further differentiated by their histopathological classification.
  • the compound of formula I can be suitable for treating diseases such as Neurofibromatosis type 1 (NF1), Noonan Syndrome with Multiple Lentigines (NSML), Noonan-like/multiple giant cell lesion syndrome, Hereditary Gingival Fibromatosis (HGF), Capillary Malformation-Arteriovenous Malformation Syndrome (CM-AVM), Legius Syndrome, Acute Staphylococcus aureus infection (Pediatric Patients), Pure mucosal neuroma syndrome, Fibrous Epulis, Acute Respiratory Distress syndrome/ Acute Lung injury and Sepsis, Costello Syndrome (CS), and Cardio-Facio-cutaneous Syndrome (CFC Syndrome).
  • diseases such as Neurofibromatosis type 1 (NF1), Noonan Syndrome with Multiple Lentigines (NSML), Noonan-like/multiple giant cell lesion syndrome, Hereditary Gingival Fibromatosis (HGF), Capillary Malformation-Arteriovenous Malformation Syndrome (CM-AVM), Legius Syndrome,
  • the compound of formula I, its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, its solvate, its combination with suitable medicament, or its pharmaceutical composition as described hereinabove may be used in therapeutic regimens in the context of first line, second fine, or any further fine of treatments.
  • the compound of formula I, its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, its solvate, its combination with suitable medicament, or its pharmaceutical composition as described hereinabove may be used for the prevention, short-tom or long term treatment of the above- mentioned diseases, optionally also in combination with radiotherapy and/or surgery.
  • the compound of formula I, its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, its solvate, belonging to the present invention can be combined with other agents such as radiation, chemotherapeutic agents and/or targeted agents in multiple cancers and their subtypes as mentioned above.
  • the agents that can be used for combination therapy include targeted agents such as inhibitors of RTKs, cyclin- dependent kinase (CDK) inhibitors, Ser-Thr kinase inhibitors, non-receptor tyrosine kinase inhibitors, inhibitors of epigenetic mechanism such as histone methyl transferases (HMTs), DNA methyl transferases (DNMTs), protein arginine methyl transferases (PRMTs), RAS inhibitors, KRAS inhibitors, MEK inhibitors, ERK1/2 inhibitors, Focal Adhesion Kinase (FAK) inhibitors, PI3K inhibitors, AKT inhibitors, and mTOR inhibitors.
  • targeted agents such as inhibitors of RTKs, cyclin- dependent kinase (CDK) inhibitors, Ser-Thr kinase inhibitors, non-receptor tyrosine kinase inhibitors, inhibitors of epigenetic mechanism such as histone methyl transferases (HMTs), DNA
  • AIBN Azobisisobutyronitrile
  • BINAP 2,2'-bis(diphenylphosphino)- 1 , 1 '-binaphthyl
  • BOP Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate
  • CAN Ceric ammonium nitrate
  • CCU Carbon tetrachloride
  • CDCU Deuterated chloroform
  • GDI l.V-Carbonyldiimidazole
  • DABCO l,4-diazabicyclo[2.2. 2]octane
  • DAST Diethylaminosulfur trifluoride
  • dba Benzylideneacetone
  • DBU 1 ,8-Diazabicyclo[5.4.0]undec-7-ene
  • DCC Dicyclohexyl carbodimide
  • DCE Dichlormethane
  • DCM Dichloromethane
  • DCM Dichloromethane
  • LCMS Liquid chromatography mass spectrometry
  • LiOH Lithium hydroxide
  • Me Methyl
  • Step-1 (R)-2-methyl-N-(l-(3-nitro-5-(trifluoromethyl)phenyl)ethylidene)propane-2-sulfinamide
  • Step-2 (R)-2-methyl-N-((R/S)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)propane-2-sulfinamide
  • Step- 1 (R)-N-( 1 -(2-fluoro-3-(trifluoromethyl)phenyl)ethylidene)-2-methylpropane-2-sulfinamide
  • the titled compound was synthesized from 1 -(2-fluoro-3 -(trifluoromethyl)phenyl)ethan- 1 -one (commercial) by following analogous reaction protocol as described in Example - 1, Step - 1 (14.1 g, 85% yield)
  • Step-2 (R/S)-N-((R)-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-2-methylpropane-2- sulfinamide
  • the titled compound was synthesized from Step - 1 intermediate by following analogous reaction protocol as described in Step- 2 of Example - 1 (5.30 g, 70% yield). It was obtained as major isomer.
  • Step-1 1 -Bromo-3 -(1,1 -difluoroethyl)-2-fluorobenzene.
  • DCM 35.0 mL
  • DAST 17.0 mL, 129 mmol
  • Reaction mixture was slowly quenched in ice water and then basified with sat. NaHCO3 solution.
  • the aqueous layer was extracted with Ethyl acetate (100.0 mL x 2).
  • Step-2 l-(3-(l,l-Difluoroethyl)-2-fluorophenyl)ethan-1-one
  • the titled compound was prepared from Step - 1 intermediate by following the analogous reaction protocol as described in Bulletin of the Chemical Society of Japan, 1987, vol. 60, # 2, p. 767 - 768 (2.0 g, 79% yield).
  • MS(ES+) m/z 202.14 (M+)
  • Step-3 (R)-N-( 1 -(3 -( 1 , 1 -difluoroethyl)-2-fluorophenyl)ethyhdene)-2-methylpropane-2-sulfinamide
  • Step-4 (R/S)-N-((R)-1-(3-( 1 , 1 -Difluoroethyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide
  • Step-6 (R/S)- 1 -(3-( 1 , 1 -Difluoroethyl)-2-fluorophenyl)ethan- 1 -amine.
  • Example - 4 Preparation of (R)-1-(3-(l-aminoethyl)-2-fluorophenyl)-l, l-difluoro-2-methylpropan-2-ol hydrochloride & (S)-1-(3-(l -aminoethyl)-2-fluorophenyl)- 1 , 1 -difluoro-2-methylpropan-2-ol hydrochloride
  • Step - 1 Ethyl 2-(3-bromo-2-fluorophenyl)-2, 2-difluoroacetate.
  • DMSO dimethyl methacrylate
  • Step - 2 l-(3-Bromo-2-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol.
  • the filtrate was evaporated under reduced pressure to afford 11.5 g crude product.
  • the crude product as such was dissolved in THF (50.0 mL) and HC1: water (1:1) (3.0 mL) was added to it at 0 °C.
  • the reaction mixture was warmed to room temperature and stirred for 15 min.
  • the reaction mixture was neutralized with saturated NaHCOs (5.0 mL) and extracted with Ethyl acetate (100.0 mL x 3).
  • the organic layer was separated, dried over anhydrous Na 2 S0 4 , and concentrated under reduced pressure.
  • the crude product obtained was purified by flash chromatography in hexane-Ethyl acetate gradient to afford the titled compound (8.8 g, 81% yield) as an oily compound.
  • Step 5 (R&S) -(R)-N-( 1 -(3 -( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)-2- methylpropane-2-sulfinamide
  • Step - 6a (R)- 1 -(3 -( 1 -Aminoethyl)-2-fluorophenyl)- 1 , 1 -difluoro-2-methylpropan-2-ol hydrochloride.
  • Step - 6b (S)-1-(3-(l-Aminoethyl)-2-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol hydrochloride.
  • Step - 1 Ethyl 2-(3-acetyl-2-fluorophenyl)-2,2-difluoroacetate Titled compound was prepared from 1 -(2-fluoro-3-iodophenyl)ethan- 1 -one using analogous protocol mentioned in Example 4-Step- 1 (4.1 g, 69.3 % yield)
  • Step 4 (R)-2-(3-(l-Aminoethyl)-2-fluorophenyl)-2,2-difluoroethan-1-ol hydrochloride
  • Step 1 N-methoxy-N-methyltetrahydrofuran-2 -carboxamide
  • Step 2 (3-BromophenylXtetrahydrofuran-2-yl)methanone To a stirred solution of 1 ,3 -dibromobenzene (6.4 mL , 53.4 mmol) in THF (50.0 mL) was slowly added nBuLi
  • Step 4 1 -(3 -(Difluoro(tetrahydrofuran-2-yl)methyl)phenyl)ethan- 1 -one.
  • Step 7 (R/S)-1-(3-(difluoro(tetrahydrofuran-2-yl)methyl)phenyl)ethan-1-amine hydrochloride
  • Step 1 (R)-N-(l-(3-(difluoromethyl)-2-methylphenyl)ethylidene)-2-methylpropane-2-sulfinamide
  • Step 2 (R)-N-((R/S)-1-(3-(difluoromethyl)-2-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide
  • Step- 1 l-bromo-3-(difluoromethyl)-5-nitrobenzene
  • Step-2 l-(3-(difluoromethyl)-5-nitrophenyl)ethan-1-one
  • Step-3 (R)-N-( 1 -(3-(difluoromethyl)-5-nitrophenyl)ethylidene)-2-methylpropane-2-sulfinamide
  • the title compound was synthesized by using step-2 intermediate and following analogous reaction protocol as described in Step - 4 of example 4.
  • Step-4 (R)-N-((R/S)-1-(3-(difluoromethyl)-5-nitrophenyl)ethyl)-2-methylpropane-2-sulfinamide
  • the titled compound was synthesized by using step-3 intermediate following analogous reaction protocol as described in Step-5 of Example 4. (1.85 g 55 % yield).
  • the titled compound was synthesized by using step-4 intermediate following analogous reaction protocol as described in Step-6 of Example 4.
  • Step-6 (R/S)-3-(l-aminoethyl)-5-(difluoromethyl)aniline
  • the titled compound was synthesized by using Step - 5 intermediate following analogous reaction protocol as described in Step - 6 of Example 3. (0.5 g, 98 % yield) as crude solid.
  • Step- 1 l-bromo-3-(l, 1 -difluoro-2-methylallyl)-2-fluorobenzene.
  • l-(3-bromo-2-fluorophenyl)-l, l-difluoro-2-methylpropan-2-ol (12.5 g, 44.2 mmol) in DCM (130.0 mL) was added Martin's Sulfurane (29.7 g, 44.2 mmol) at room temperature. The reaction mixture was stirred at same temperature for 30 min.
  • Step- 2 3-(3-bromo-2-fluorophenyl)-3, 3-difluoro-2-methylpropane-l, 2-diol
  • Step- 3 (S/R)-1-(3-(l, l-difluoro-2, 3-dihydroxy-2-methylpropyl)-2-fluorophenyl) ethan-1-one (Peak-1) and (R/S)-1-(3-(l, l-difluoro-2, 3-dihydroxy-2-methylpropyl)-2-fluorophenyl) ethan-1-one (Peak2)
  • the titled compounds were synthesized by following analogous reaction protocol as described in Step-3 of Example-4 preparation using 3-(3-bromo-2-fluorophenyl)-3,3-difluoro-2-methylpropane-l,2-diol and further separated by chiral chromatography (Instrument Method: MEOH_0.1 %DEA_100_B_1.0 ML _8MIN Flow Rate: 1.00 mL /min) to afford two isomers as Peak 1 (1.25g, 41% yield) & Peak 2 (1.35 g, 45% yield) respectively.
  • Step- 4 (R)-N-(l-(3-((S/R)-1,1-difluoro-2,3-dihydroxy-2-methylpropyl)-2-fluorophenyl)ethylideiie)-2- methylpropane-2-sulfinamide (Peak 1) and (R)-N-(l-(3-((R/S)-1,1-difluoro-2,3-dihydroxy-2-methylpropyl)- 2-fluorophenyl)ethylidene)-2-methylpropane-2-sulfinamide (Peak 2)
  • the titled compounds were synthesized from Step - 3 intermediate by following analogous reaction protocol as described in Step - 4 of Example 4 (Peak 1 & Peak 2 respectively).
  • (Peak-l) (1.60 g, 63% yield)
  • Step- 5a (R)-N-((R/S)-1-(3-((R/S)-1,1-difluoro-2,3-dihydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)-2- methylpropane-2-sulfinamide
  • the titled compounds were synthesized from Step - 4 intermediate by following analogous reaction protocol mentioned in Step-5 of Example 4 (Peak 1) (0.45 g, 37% yield).
  • Step 5b (R)-N-((R/S)-1-(3-((S/R)-1,1-difluoro-2,3-dihydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)-2- methylpropane-2-sulfinamide
  • Step- 6a (R/S)-3-(3-((R/S)-1-aminoethyl)-2-fluorophenyl)-3,3-difluoro-2-methylpropane-l,2-diol hydrochloride
  • Step 6b (S/R)-3-(3-((S/R)-1-aminoethyl)-2-fluorophenyl)-3,3-difluoro-2-methylpropane-l,2-diol hydrochloride
  • Step - 2 l-(3-(l,l -Difluoro-2-hydroxy-2-methylpropyl)phenyl)ethan- 1 -one
  • Step - 3 (R)-N-(l-(3-(l,l-Difluoro-2-hydroxy-2-methylpropyl)phenyl)ethylidene)-2-methylpropane-2- sulfinamide
  • the titled compounds were synthesized from Step - 2 intermediate by following analogous reaction protocol as described in Step - 4 of Example 4. (4.0 g, 72.5% yield)
  • Step 4 (R/S)-2-methyl-N-((R/S)- 1-(3-( 1 , 1 ,2,2-tetrafluoro-2-hydroxyethyl)phenyl)ethyl)propane-2- sulfinamide
  • Step - 5 (R/S)-1-(3-(l-Aminoethyl)phenyl)-1,1-difluoro-2-methylpropan-2-ol hydrochloride
  • Step-3 (R/S)-2-(3-(l-Aminoethyl)-2-methylphenyl)-2,2-difluoroethan- l-ol hydrochloride
  • Step-1 (R)-N-((R/S)-1-(3,3-Difluoro-2,3-dihydrobenzofuran-7-yl)ethyl)-2-methylpropane-2-sulfinaniide
  • (R)-N-((R/S)-1-(3-(l,l-difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)-2- methylpropane-2-sulfinamide 1.0 g, 3.09 mmol
  • Step - 3 product of Example 5 was added 18 -crown- 6 (0.409 g, 1.546 mmol) and cesium carbonate (3.02 g, 9.28 mmol) under nitrogen atmosphere and heated the reaction mass at 80 °C for 16 h.
  • Step-2 (R/S)-1-(3,3-Difluoro-2,3-dihydrobenzofuran-7-yl)ethan-1-aniine
  • the titled compound was synthesized from Step-1 intermediate by following analogous reaction protocol as described in Step 6 of Example 4 (0.35 g, 90% yield).
  • Example 13 Synthesis of (R/S)-2-(3-((S/R)-1-aminoethyl)-2-fluorophenyl)-3,3,3-trifluoropropane-l,2-diol hydrochloride Step 1: l-Bromo-2-fluoro-3-(3,3,3-trifluoroprop-1-en-2-yl)benzene
  • Peak-2 (3.4 g 41% yield, T ret -4.73min, chiral purity: 99.85)
  • Step 4a (R)-N-((R/S)-1-(3-((R/S)-1,1-difluoro-2,3-dihydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)-2- methylpropane-2-sulfinamide
  • Step 4b (R)-N-((R/S)-1-(3-((S/R)-1,1-difluoro-2,3-dihydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)-2- methylpropane-2-sulfinamide
  • Step 5a (R/S)-3-(3-((R/S)-1-aminoethyl)-2-fluorophenyl)-3,3-difluoro-2-methylpropane-l,2-diol hydrochloride
  • the titled compounds woe synthesized by using step 4a intermediate following analogous reaction protocol as described in Step - 6 of Example 4 (0.55 g , 96% yield)
  • Step 5b (R/S)-3-(3-((S/R)-1-aminoethyl)-2-fluorophenyl)-3,3-difluoro-2-methylpropane-l,2-diol hydrochloride
  • reaction mixture was quenched in water (100.0 mL) and extracted with ethyl acetate (150.0 mL), the organic layer was washed with water (100.0 ml), brine (100.0 mL) and dried over anhydrous Na 2 S0 4 , filtered and concentrated in vacuo to give crude compound.
  • This crude residue was purified by flash chromatography using eluent 0 - 30% ethyl acetate in n-hexane to afford the title compound methyl 4-methyl-7-nitro-3-oxo-3,4- dihydro-2H-benzo[b][l,4] oxazine-6-carboxylate (1.6 g, 76.0 % yield) as an off white solid.
  • GCMS m/z 266.05 (M+).
  • Step 5 (R)-4-((l-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2,6-dimethyl-6H-[l,4]oxazino[3,2- g]quinazolin-7(8H)-one
  • DMF 1,5-dimethyl-3,6-dihydro-4H-[l,4]oxazino[3,2-g]quinazoline-4,7(8H)-dione
  • reaction mass was concentrated in vacuo to give crude compound.
  • This crude residue was purified by flash chromatography using eluent 0 - 4% methanol in DCM to afford the title compound (R)-4-((l-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2, 6-dimethyl- 6H-[l,4]oxazino[3,2-g]quinazolin-7(8H)-one (0.36 g, 51.2 % yield) as an off white solid.
  • Step 2 (R&S)-Methyl 7-amino-3-oxo-4-((tetrahydrofuran-3-yl)methyl)-3,4-dihydro-2H-benzo[b] [ 1 ,4]oxazine-6-carboxylate
  • the titled compound was prepared from Step 2 intermediate by employing similar protocol mentioned in Example 14 Step 4 (0.6 g, 72.90 % yield).
  • Step 4 (R&S)- 4-(((R)-1-(3-amino-5(trifluoromethyl)phenyl)ethyl)aniino)-2-methyl-6-((tetrahydrofuran-3- yl)methyl)-6H-[l,4]oxazino[3,2-g]quinazolin-7(8H)-one.
  • Compound 11 The titled compound was prepared from Step 3 intermediate by employing similar protocol mentioned in
  • Step 1 Methyl 4-(cyclopropylmethyl)-7-nitro-3-oxo-3,4-dihydro-2H-benzo[b][l,4]oxazine-6-carboxylate
  • the titled compound was prepared from Example 14 Step 1 intermediate & (bromomethyl) cyclopropane by employing similar protocol mentioned in Example 14 Step 2 (1.69 g, 93.0 % yield)
  • Step 2 Methyl 7 -amino-4-(cyclopropylmethyl)-3 -oxo-3 ,4-dihydro-2H-benzo[b] [ 1 ,4]oxazine-6-carboxylate
  • the titled compound was prepared from Step 1 intermediate by employing similar protocol mentioned in Example 14 Step 3 (1.61 g, 100%) crude yield.
  • Step 4 (R)-4-((l-(3-amino-5-(trifluoromethyl)phenyl)ethyl)aniino)-6-(cyclopropylmethyl)-2-methyl-6H- [l,4]oxazino[3,2-g]quinazolin-7(8H)-one (Compound 12 )
  • the titled compound was prepared from Step 3 intermediate by employing similar protocol mentioned in Example 14 Step 5 (0.51 g, 78.0 % yield).
  • Step 1 Methyl 4-ethyl-7-nitro-3-oxo-3,4-dihydro-2H-benzo[b][l,4]oxazine-6-carboxylate
  • the titled compound was prepared from Example 14 Step 1 intermediate by employing similar protocol mentioned in Example 14 Step 2 (4.36 g, 78.0 % yield).
  • Step 2 Methyl 7-amino-4-ethyl-3-oxo-3 ,4-dihydro-2H-benzo[b] [ 1 ,4]oxazine-6-carboxylate.
  • the titled compound was prepared from Step 1 intermediate by employing similar protocol mentioned in Example 14 Step 3 (3.2 g, 90.0% yield).
  • Step 3 6-Ethyl-2-methyl-3,6-dihydro-4H-[l,4]oxazino[3,2-g]quinazohne-4,7(8H)-dione
  • the titled compound was prepared from Step 2 intermediate by employing similar protocol mentioned in Example 14 Step 4 (2.71 g, 84.0 % yield).
  • Step 4 (R)-4-((l-(3-(l,l-difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)aniino)-6-ethyl-2-methyl-6H- [l,4]oxazino[3,2-g]quinazolin-7(8H)-one. (Compound 13)
  • the titled compound was prepared by reaction of Step 3 intermediate and appropriate amine using similar protocol mentioned in Example 14 Step 5 (0.028 g, 8.0% yield).
  • Example 14 Step 3 The titled compound was prepared from Example 14 Step 3 intermediate & propionitrile by employing similar protocol mentioned in Example 14 Step 4 (1.4 g, 85.0% yield).
  • Step 2 (R)-4-((l-(3-amino-5-(trifluoromethyl)phenyl)ethyl)ainmo)-2-ethyl-6-methyl-6H-[l,4]oxazino[3,2- g]quinazolin-7(8H)-one.
  • the titled compound was prepared from Step 1 intermediate by employing similar protocol mentioned in Example 14 Step 5 (0.09 g, 18.5% yield).
  • Step 1 4-Chloro-2-ethyl-6-methyl-6H-[l,4]oxazino[3,2-g]quinazolin-7(8H)-one
  • Step 2 (R)-4-((l-(3-(1,1-difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)amino)-2-ethyl-6-methyl-6H-
  • Step 1 2-Cyclopropyl-6-methyl-3,6-dihydro-4H-[l,4]oxazino[3,2-g]quinazoline-4,7(8H)-dione
  • Example 14 Step 3 The titled compound was prepared from Example 14 Step 3 intermediate & cyclopropane carbonitrile by employing similar protocol mentioned in Example 14 Step 4 (1.02 g, 59.2% yield).
  • Step 2 4-Chloro-2-cyclopropyl-6-methyl-6H-[ 1 ,4]oxazino[3 ,2-g]quinazolin-7(8H)-one
  • the titled compound was prepared from Step 1 intermediate by employing similar protocol mentioned in Example 28 Step 1 (0.62 g, 58.0% yield).
  • Step 3 (R)-2-cyclopropyl-4-((l-(3-( 1 , 1 -difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)animo)-6-methyl-6H- [ 1 ,4]oxazino[3,2-g]quinazolin-7(8H)-one (Compound-16)
  • the titled compound was prepared by reaction of Step 2 intermediate and appropriate amine using similar protocol mentioned in Example 28 Step 2 (0.021 g, 13.0% yield).
  • Example 30 Preparation of (R&S)-(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl- 8,9-dihydro-7H-pyrano[2,3-g]quinazolin-7-yl)(pyrrolidin-1-yl)methanone (Compound 17a and 17b) Step 1: l-(5-Bromo-2-hydroxy-4-methylphenyl)ethan-1-one.
  • Step 2 Ethyl 6-bromo-7 -methyl-4 -oxo-4H-chromene-2-carboxylate
  • l-(5-bromo-2-hydroxy-4-methylphenyl)ethan-1-one 1.1 g, 4.80 mmol
  • diethyl oxalate 1.97 mL, 14.41 mmol
  • DMF 5.0 mL
  • potassium tert butoxide 39.2 g, 349.0 mmol
  • Step 4 Ethyl 6-bromo-7-formyl-4-oxo-4H-chromene-2-carboxylate
  • acetonitrile 100.0 mL
  • 4-methyl-4-oxidomorpholin- 4-ium 10.51 g, 90 mmol
  • Step 8 2-Methyl-7-(pyrrolidine-1-carbonyl)-3H-pyrano[2,3-g]quinazoline-4,9-dione
  • Step 9 (R&S) -(4-Hydroxy-2-methyl-8,9-dihydro-7H-pyrano[2,3-g]quinazolin-7-yl)(pyrrolidin-1-yl) methanone
  • Step 10 (R&S)-(4-Chloro-2-methyl-8,9-dihydro-7H-pyrano[2,3-g]quinazolin-7-yl)(pyrrolidin-1-yl) methanone
  • the titled compound was prepared from Step 9 intermediate by employing similar protocol mentioned in Example 28 Step 1 (0.13 g, 79.0% yield).
  • Step 11 Preparation of (R&S)-(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)aniino)-2-methyl-8,9- dihydro-7H-pyrano[2,3-g]quinazolin-7-ylXpynolidin-1-yl)methanone.
  • the titled compound was prepared by reaction of Step 10 intermediate and appropriate chiral amine using analogous protocol mentioned in Example 28 Step 2 (0.15g, 13.0% yield).
  • Diastereomer formed in this product was separated by reverse phase preparative HPLC Peak 1 : ((R/S)-4-(((R)- l-(3-amino-5-(trifluoromethyl)phenyl)ethyl)aniino)-2-methyl-8,9-dihydro-7H- pyrano[2,3-g]quinazohn-7-ylXpynolidin-1-yl)methanone.
  • Example 31 Preparation of (R)-4-((l-(3-( 1 , l-difhioro-2-hydroxyethyl)-2-fluorophenyl)ethyl)amino)-2,6,8,8- tetramethyl-6H-[l,4]oxazino[3,2-g]quinazolin-7(8H)-one (Compound 18) Step 1: Methyl 2,2-dimethyl-7-nitro-3-oxo-3,4-dihydro-2H-benzo[b][l,4]oxazine-6-carboxylate.
  • Step 3 Methyl 7-amino-2,2,4-trimethyl-3-oxo-3,4-dihydro-2H-benzo[b][l,4]oxazine-6-carboxylate
  • Step 4 2,6,8,8-Tetramethyl-3,6-dihydro-4H-[l,4]oxazino[3,2-g]quinazoline-4,7(8H)-dione
  • the titled compound was prepared from Step 3 intermediate by employing similar protocol mentioned in Example 14 Step 4 (3.1 g, 86 % yield).
  • the titled compound was prepared from Step 4 intermediate by employing similar protocol mentioned in Example 28 Step 1 (0.35 g, 65.6 % yield).
  • Example 35 4-(((R&S)- 1 -(2-Fluoro-3-((R&S)- 1,1,1 -trifluoro-2,3 -dihydroxypropan-2- yl)phenyl)ethyl)amino)-2,6,8,8-tetramethyl-6H-[l,4]oxazino[3,2-g]quinazolin-7(8H)-one
  • Example 31 Step 5 The titled compound as a diastereomeric mixture was prepared from Example 31 Step 5 intermediate by employing similar protocol mentioned in Example 28 Step 2.
  • Peak 2 4-(((R/S)-1-(2-fluoro-3-((R/S)- 1 , 1 ,l-trifluoro-2,3-dihydroxypropan-2-yl)phenyl)ethyl)aniino)- 2,6,8,8-tetramethyl-6H-[l,4]oxazino[3,2-g]quinazolin-7(8H)-one (Compound 22b)
  • Example 31 Step 5 & Example 13 Step 5b intermediate by employing similar protocol mentioned in Example 28 Step 2.
  • Example 36 4-(((R&S)-1-(3-((R&S)-1,1-difluoro-2,3-dihydroxy-2-methylpropyl)-2- fluorophenyl)ethyl)amino)-2,6,8,8-tetramethyl-6H-[l,4]oxazino[3,2-g]quinazolin-7(8H)-one (Compound 23)
  • Example 31 Step 5 The titled compound as a diastereomeric mixture was prepared from Example 31 Step 5 intermediate by employing similar protocol mentioned in Example 28 Step 2
  • Peak 2 4-(((R/S)-1-(3-((R/S)-1,1-difluoro-2,3-dihydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)aniino)- 2,6,8,8-tetramethyl-6H-[l,4]oxazino[3,2-g]quinazolin-7(8H)-one. (Compound 23b)
  • Example 31 Step 5 & Example 9 Step 6b intermediate by employing similar protocol mentioned in Example 28 Step 2.
  • Example 34 The titled compound was prepared from Example 34 by employing similar protocol mentioned in Example 23 (0.017 g, 11.69 % yield).
  • Step 1 Methyl 3 -oxo-3 ,4-dihydrospiro[berizo[b] [ 1 ,4]oxazine-2, 1 -cyclopropane] -6-carboxylate
  • Step 2 Methyl 7-nitro-3-oxo-3,4-dihydrospiro[benzo[b][l,4]oxazine-2,l'-cyclopropane]-6-carboxylate
  • Step 3 Methyl 4-methyl-7-nitro-3-oxo-3,4-dihydrospiro[benzo[b][l,4]oxazine-2,l'-cyclopropane]-6- carboxylate
  • the titled compound was prepared from Step 2 intermediate by employing similar protocol mentioned in Example 14 Step 2 (0.91 g, 61.9 % yield).
  • the titled compound was prepared from Step 3 intermediate by employing similar protocol mentioned in Example 14 Step 3 (0.8 g, 99.0 % yield).
  • Step 5 2 , ,6 , -Dimethyl-3 , ,6 , -dihydrospiro[cyclopropane-l,8'-[l,4]oxazino[3,2-g]quinazoline]-4 , ,7 , -dione
  • the titled compound was prepared from Step 4 intermediate by employing similar protocol mentioned in Example 14 Step 4 (0.19 g, 22.96 % yield).
  • Step 6 4 , -Chloro-2 , ,6'-dimethylspiro[cyclopropane- 1 ,8'-[ 1 ,4]oxazino[3,2-g]quinazolin] -7'(6H)-one
  • the titled compound was prepared from Step 5 intermediate by employing similar protocol mentioned in Example 28 Step 1 (0.12 g, 65.0 % yield).
  • Step 7 (R)-4'-(( 1 -(3-(l , 1 -difluoro-2-hydroxyethyl)-2-fluo ⁇ ophenyl)ethyl)amino)-2 , ,6 , - dimethylspiro[cyclopropane-l,8'-[l,4]oxazino[3,2-g]quinazolin]-7'(6'H)-one (Compound 25)
  • the titled compound was prepared from Step 6 intermediate and appropriate chiral amine by employing similar protocol mentioned in Example 28 Step 2 (0.05g, 21.96% yield).
  • Step 1 Methyl 2,2-dimethyl-3-morpholino-7-nitro-2H-benzo[b][l,4]oxazine-6-carboxylate.
  • Step 2 Methyl 7-amino-2,2-dimethyl-3-morpholino-2H-benzo[b][l,4]oxazine-6-carboxylate
  • the titled compound was prepared from Step 1 intermediate by employing similar protocol mentioned in Example 14 Step 3 (1.8 g, 82.0% yield).
  • MS (ES+) m/z 320.22 (M+l).
  • the titled compound was prepared from Step 2 intermediate by employing similar protocol mentioned in Example 14 Step 4 (0.8 g, 51.9 % yield).
  • Step 4 4-Chloro-2,8,8-trimethyl-7-morpholino-8H-[l,4]oxazino[3,2-g]quinazoline
  • Step 5 (R)-1,1-Difluoro-1-(2-fluoro-3-(l-((2,8,8-trimethyl-7-morpholino-8H [l,4]oxazino[3,2-g] quinazolin- 4-yl)amino)ethyl)phenyl)-2-methylpropan-2-ol. (Compound 26)
  • the titled compound was prepared by reaction of Step 4 intermediate and (R)-1-(3-(l-Aminoethyl)-2- fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol hydrochloride (Example 4-Step 6a) using similar protocol mentioned in Example 28 Step 2 (0.08 lg, 33.6 % yield).

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  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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WO2022161480A1 (zh) * 2021-02-01 2022-08-04 苏州泽璟生物制药股份有限公司 取代双环并芳杂环胺类抑制剂及其制备方法和应用
WO2022207673A1 (en) 2021-03-31 2022-10-06 Sevenless Therapeutics Limited Sos1 inhibitors and ras inhibitors for use in the treatment of pain
WO2022214594A1 (en) 2021-04-09 2022-10-13 Boehringer Ingelheim International Gmbh Anticancer therapy
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WO2023060253A1 (en) 2021-10-08 2023-04-13 Revolution Medicines, Inc. Ras inhibitors
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WO2023135260A1 (en) 2022-01-14 2023-07-20 Jazz Pharmaceuticals Ireland Limited Novel amine-substituted phthalazines and derivatives as sos1 inhibitors
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US11964977B2 (en) 2020-05-29 2024-04-23 Boehringer Ingelheim Animal Health USA Inc. Anthelmintic heterocyclic compounds
WO2022060836A1 (en) 2020-09-15 2022-03-24 Revolution Medicines, Inc. Indole derivatives as ras inhibitors in the treatment of cancer
WO2022121813A1 (zh) * 2020-12-07 2022-06-16 北京泰德制药股份有限公司 Sos1抑制剂、包含其的药物组合物及其用途
WO2022157629A1 (en) * 2021-01-19 2022-07-28 Lupin Limited Pharmaceutical combinations of sos1 inhibitors for treating and/or preventing cancer
WO2022161480A1 (zh) * 2021-02-01 2022-08-04 苏州泽璟生物制药股份有限公司 取代双环并芳杂环胺类抑制剂及其制备方法和应用
WO2022207673A1 (en) 2021-03-31 2022-10-06 Sevenless Therapeutics Limited Sos1 inhibitors and ras inhibitors for use in the treatment of pain
WO2022214594A1 (en) 2021-04-09 2022-10-13 Boehringer Ingelheim International Gmbh Anticancer therapy
WO2022222875A1 (zh) * 2021-04-19 2022-10-27 昆药集团股份有限公司 一种苯并嘧啶三环衍生物及其制备方法和应用
TWI807787B (zh) * 2021-04-19 2023-07-01 大陸商昆藥集團股份有限公司 苯並嘧啶三環衍生物及製備方法和應用
WO2023060253A1 (en) 2021-10-08 2023-04-13 Revolution Medicines, Inc. Ras inhibitors
US11999742B2 (en) 2021-11-01 2024-06-04 Boehringer Ingelheim Vetmedica Gmbh Substituted pyrrolo[1,2-b]pyridazines as anthelmintics
CN115536660A (zh) * 2021-11-04 2022-12-30 北京福元医药股份有限公司 苄氨基取代的杂多环化合物及其组合物、制剂和用途
WO2023109929A1 (zh) * 2021-12-17 2023-06-22 石药集团中奇制药技术（石家庄）有限公司 一种具有抗肿瘤活性的杂环化合物及其用途
WO2023114954A1 (en) 2021-12-17 2023-06-22 Genzyme Corporation Pyrazolopyrazine compounds as shp2 inhibitors
WO2023135260A1 (en) 2022-01-14 2023-07-20 Jazz Pharmaceuticals Ireland Limited Novel amine-substituted phthalazines and derivatives as sos1 inhibitors
WO2023153748A1 (ko) * 2022-02-10 2023-08-17 (주)파로스아이바이오 Sos1 억제제 및 이의 유도체
EP4227307A1 (en) 2022-02-11 2023-08-16 Genzyme Corporation Pyrazolopyrazine compounds as shp2 inhibitors
WO2023165438A1 (zh) * 2022-03-03 2023-09-07 浙江海正药业股份有限公司 三环类衍生物及其制备方法和用途
WO2023180345A1 (en) 2022-03-22 2023-09-28 Jazz Pharmaceuticals Ireland Limited Tricyclic phthalazines and derivatives as sos1 inhibitors
WO2023230205A1 (en) 2022-05-25 2023-11-30 Ikena Oncology, Inc. Mek inhibitors and uses thereof
WO2023240263A1 (en) 2022-06-10 2023-12-14 Revolution Medicines, Inc. Macrocyclic ras inhibitors

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